Proteopedia - User contributions [en]

Sandbox Reserved 773

2013-12-04T02:51:39Z

Wesley Yang: /* Enzymatic Mechanism */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belong in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>. Since this enzyme breaks the carbon-carbon bond to produce carbon dioxide (CO2), it is in class IV lyase.

The mammalian Histamine decarboxylase is originated from HDC gene which in found in the human chromosome 15. This gene encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helices/1'>helices</scene> and 13% <scene name='56/564049/Sheets/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long <scene name='56/564049/Long/1'>α-helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/2'>catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The <scene name='56/564049/Hydrophobic/1'>hydrophobic pocket</scene> of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and dipole moments create a stable environment for PLP to stay in place during the transitional state through proximity effect.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-04T00:46:11Z

Wesley Yang: /* Histidine Decarboxylase */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belong in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>. Since this enzyme breaks the carbon-carbon bond to produce carbon dioxide (CO2), it is in class IV lyase.

The mammalian Histamine decarboxylase is originated from HDC gene which in found in the human chromosome 15. This gene encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helices/1'>helices</scene> and 13% <scene name='56/564049/Sheets/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long <scene name='56/564049/Long/1'>α-helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/2'>catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The <scene name='56/564049/Hydrophobic/1'>hydrophobic pocket</scene> of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:30:59Z

Wesley Yang: /* Cofactor and Substrate Binding Pocket */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helices/1'>helices</scene> and 13% <scene name='56/564049/Sheets/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long <scene name='56/564049/Long/1'>α-helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/2'>catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The <scene name='56/564049/Hydrophobic/1'>hydrophobic pocket</scene> of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:26:01Z

Wesley Yang: /* Cofactor and Substrate Binding Pocket */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helices/1'>helices</scene> and 13% <scene name='56/564049/Sheets/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long <scene name='56/564049/Long/1'>α-helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The <scene name='56/564049/Hydrophobic/1'>hydrophobic pocket</scene> of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:18:55Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helices/1'>helices</scene> and 13% <scene name='56/564049/Sheets/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long <scene name='56/564049/Long/1'>α-helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:18:29Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helices/1'>helices</scene> and 13% <scene name='56/564049/Sheets/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively <scene name='56/564049/Long/1'>long α-helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:15:25Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helices/1'>helices</scene> and 13% <scene name='56/564049/Sheets/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:10:46Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Sdomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:04:30Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/3'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T14:00:57Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterminal/1'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T13:56:22Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/5'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T13:47:53Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/2'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T13:42:06Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/3'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T13:25:39Z

Wesley Yang: /* Cofactor and Substrate Binding Pocket */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The <scene name='56/564049/Binding/1'>Catalytic site</scene> for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T13:13:17Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> (7 antiparallel and 4 parallel β-sheets)<ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T13:12:45Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> <ref name=4e10/> (7 antiparallel and 4 parallel β-sheets). One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene> which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T13:05:54Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> <ref name=4e10/>. One distinctively long α-<scene name='56/564049/Longhelix/1'>helix</scene>which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T12:58:40Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/2'>helices</scene> and 13% <scene name='56/564049/Sheet/1'>sheets</scene> <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T12:53:54Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% <scene name='56/564049/Helix/1'>helices</scene> and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T12:36:30Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer in the [[asymmetric unit]] which can be seen in the 3D <scene name='56/564049/Front/1'>model</scene> <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are found to account for the oligomerization process of the HDC complex<ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T12:30:47Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and <scene name='56/564049/Cys418/1'>Cys-418</scene> are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T12:22:44Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, <scene name='56/564049/Cys180/1'>Cys-180</scene> and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T11:52:34Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/2'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T11:42:44Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: the <scene name='56/564049/Nterm/4'>N-terminal</scene> (~2-71), the <scene name='56/564049/Largedomain/2'>large domain</scene> (71-371), and the <scene name='56/564049/Smalldomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T11:35:12Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/4'>domains</scene>. They are: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), <scene name='56/564049/Largedomain/1'>large domain</scene> (71-371), and <scene name='56/564049/Smalldomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T10:53:03Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/3'>domains</scene>. They are: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), <scene name='56/564049/Largedomain/1'>large domain</scene> (71-371), and <scene name='56/564049/Smalldomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T10:13:03Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/3'>domains</scene>: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), <scene name='56/564049/Largedomain/1'>large domain</scene> (71-371), and <scene name='56/564049/Smalldomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T09:57:43Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), <scene name='56/564049/Largedomain/1'>large domain</scene> (71-371), and <scene name='56/564049/Smalldomain/1'>small domain</scene> (372-477) (Figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T09:55:49Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), <scene name='56/564049/Largedomain/1'>large domain</scene> (71-371), and <scene name='56/564049/Smalldomain/1'>small domain</scene> (372-477) (figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T09:55:20Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), <scene name='56/564049/Largedomain/1'>large domain</scene> (71-371), and <scene name='56/564049/Smalldomain/1'>TextToBeDisplayed</scene> (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T09:51:31Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), <scene name='56/564049/Largedomain/1'>large domain</scene> (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T09:34:36Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: <scene name='56/564049/Nterm/2'>N-terminal</scene> (~2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T09:16:41Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: <scene name='56/564049/Nterm/1'>N-terminal</scene> (~2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T09:15:42Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: <scene name='56/564049/Nterm/1'>N-terminal</scene> (~2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T08:29:07Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains.

Each monomer is divided into 3 structural <scene name='56/564049/3domain/1'>domains</scene>: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T07:39:08Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One distinctively long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T07:23:56Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homodimer is a [[quaternary structure]] formed by two identical monomers or protein chains.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-02T07:22:50Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

In human, three human HDC (hHDC) homodimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T07:04:32Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cys-180 and Cys-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Val-359 to Arg-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:54:35Z

Wesley Yang:

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Asymmetric unit of Histidine Decarboxylase complex with 6 PLP-HME substrate-analogs (atoms shown in orange, grey, and blue) bound to each of the active sites.' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:47:05Z

Wesley Yang: /* General Information */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=4e10/> <ref name=uniprot/>

'''Gene Name''': HDC gene <ref name=4e10/> <ref name=uniprot/>

'''Organism''': Homo sapiens <ref name=4e10/> <ref name=uniprot/>

'''Classification''': Lyase <ref name=4e10/> <ref name=uniprot/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:46:28Z

Wesley Yang: /* General Information */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC <ref name=uniprot/> <ref name=4e10/>

'''Gene Name''': HDC gene <ref name=uniprot/> <ref name=4e10/>

'''Organism''': Homo sapiens <ref name=uniprot/> <ref name=4e10/>

'''Classification''': Lyase <ref name=uniprot/> <ref name=4e10/>

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:41:15Z

Wesley Yang:

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Pathways and Implications==

Histidine Decarboxylase is a rather unstable enzyme with a short half-life of 50-100 min in varous conditions <ref name=fun/>. This enzyme is only synthesized when histamine is needed and quickly degraded when enough histamine is made by Histamine N-methyltransferase (HMT) and Diamine oxidase (DAO) <ref name=metabolism/>.

Furthermore, not all cells are found to make histamine. So far, only mask cells <ref name=mast/>, basophils <ref name=metabolism/>, neutrophil <ref name=neut>PMID: 23572231</ref>, enterochromafflin-like cells in gastric mucosa <ref name=tour/>, and histaminergic neuron <ref name=metabolism/> generate and store histamine. The histamine usually stored in the granula of these cells <ref name=metabolism/>. Research have found that epithelial cell and lymphocytes can express HDC and synthesize histamine but cannot store them <ref name=metabolism/>.

During a stimulation, the histamine are released in large amount which triggers many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref>PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:36:35Z

Wesley Yang: /* Implications */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Implications ==

Histamine is a key mediator which is associated with many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref> PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:36:15Z

Wesley Yang: /* Implications */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Implications ==

Histamine is a key mediator which is associated with many physiological process including:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref> PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capillary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- neurotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome* <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:29:33Z

Wesley Yang: /* Histidine Decarboxylase */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Implications ==

Histamine is a key factor which relates to many physiological process. Some of these affected physiological process are listed below:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref> PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capiliary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- Nuerotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of Neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome* <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:29:15Z

Wesley Yang: /* Sequence and Structure */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Implications ==

Histamine is a key factor which relates to many physiological process. Some of these affected physiological process are listed below:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref> PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capiliary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- Nuerotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of Neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome* <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:28:56Z

Wesley Yang: /* Cofactor and Substrate Binding Pocket */

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Implications ==

Histamine is a key factor which relates to many physiological process. Some of these affected physiological process are listed below:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref> PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capiliary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- Nuerotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of Neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome* <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T06:28:10Z

Wesley Yang:

{{User:Michael_B._Goshe/Template_BCH455_555}}


= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

__TOC__

== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== Implications ==

Histamine is a key factor which relates to many physiological process. Some of these affected physiological process are listed below:

- Allegoric reaction and Inflammation response <ref name=dev>PMID: 18650915</ref>

- Gastric acid secretion <ref> PMID: 10461351</ref> <ref name=autoanti>PMID: 12679420</ref>

- Capiliary dilation and smooth muscle contraction <ref name=dev/>

- Immune response <ref name=trend>PMID: 12102747</ref>

- Nuerotansmission in CNS <ref name=arousal>PMID:4011742</ref> <ref name=tour/>

One of the most important role histamine play is the role of Neurotransmitter in the central nervous system (CNS). When HDC is inhibited to function, it can change histaminergic neuron mediated physiological response listed below, as well as contributes to the probability for multiple diseases:

- Arousal <ref name=arousal/> <ref name=sleep>PMID: 12196593</ref>

- Appetite <ref name=app>PMID: 10604837</ref>

- Locomotion <ref name=app/>

- Tourette syndrome* <ref name=tour>PMID: 20445167</ref>

- Schizophrenia <ref name=fun/>

However outside of the central nervous system, anti-histamine drugs or HDC inhibitors are useful for treatment against allergic reaction, gastric ulcer, and inflammation <ref name=fun/> <ref name=jbc/>

== References ==
{{reflist}}

Sandbox Reserved 773

2013-12-01T03:05:37Z

Wesley Yang: /* Histidine Decarboxylase */

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= Histidine Decarboxylase =
[[Image:4e1o asr r 500.jpg|frame|right|Figure 1. Asymmetrical unit of Histidine Decarboxylase formed by 3 homodimer-subunits)]]

'''Histidine Decarboxylase (HDC)''' is an enzyme that is responsible for converting histamine from amino acid L-histidine. This enzyme belongs in the group II pyridoxal-5-phosphate (PLP)-dependent decarboxylase family <ref name=fun/>. As the name suggested, this enzyme catalyzes the production of histamine by the removal of carboxylate group from the amino acid L-histidine whilst utilizes on pyridoxal phosphate as a cofactor <ref name=metabolism/>

The mammalian Histamine decarboxylase is originated from HDC gene which encodes a 74kDa precursor polypeptide <ref name=tag>PMID: 6425286</ref>. However, the enzyme becomes active after undergo post-translation proteolysis when its C-terminal is truncated into 54kDa <ref name=metabolism>Schwelberger, Hubert G. "Metabolism of Histamine." ''European Histamine Research Society'' Nov. 2013. Web. 29 Nov. 2013. http://www.ehrs.org.uk/schwelberger.pdf</ref> <ref name=jbc/>.

Due to the fact that histamine is a mediator that triggers inflammation response associated with allergic reaction, HDC an important enzyme to study for the development of drugs or treatments for allergic disease <ref name=fun>PMID: 15612036</ref> <ref name=metabolism/>.

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== General Information ==
'''Histidine Decarboxylase'''

[[Image:Histidine decarboxylase seq.png|thumb|right|Figure 2. Sequence of Histidine Decarboxylase with its corresponding secondary stuctures <ref name=4e10/>]]

'''Symbol''': HDC

'''Gene Name''': HDC gene

'''Organism''': Homo sapiens

'''Classification''': Lyase

'''Length''': 481 residues <ref name=4e10>"Human Histidine Decarboxylase Complex with Histidine Methyl Ester (HME)." ''RSCB Protein Data Bank. RCSB.'' Web. 29 Nov. 2013. <http://www.rcsb.org/pdb/explore/explore.do?structureId=4E1O>.</ref>

'''Chains''': A, B, C, D, E, F <ref name=4e10/>

'''Molecular Weight''': 54314.8 kDa per chain <ref name=4e10/>

'''Isoelectric Point''': 5.4 (mouse HDC) <ref name=stomach>PMID: 1540215</ref> <ref name=mast>PMID: 2118138</ref>

'''Km''': 0.1 mM (human) <ref name=jbc> PMID: 22767596</ref> <ref name=uniprot>"P19113 (DCHS_HUMAN)." ''UniProt. Protein Knowledgebase.'' Web. 29 Nov. 2013 <http://www.uniprot.org/uniprot/P19113>.</ref>, 0.29mM (mouse stomach) <ref name=stomach/>, 0.26mM (mouse mastocytoma P-815 cells) <ref name=mast/>

'''Vmax''': 1880 nmol/min/mg

== Sequence and Structure ==

Histidine Decarboxylase is considered to be a homo-dimer when one observe its [[biological assembly]] <ref name=mast/>. A homo-dimer is a [[quaternary structure]] formed by two identical monomers or protein chains. In human, three human HDC (hHDC) homo-dimers can be joined together to form a trimer [[asymmetric unit]] <ref name=jbc/> <ref name=xray>PMID: 22684068</ref>. Thus, one can use the nomenclature “trimer of dimer” to suggest the complex might dissociate into smaller subunits before dissociating into monomers. The asymmetrical unit can be seen in Figure 1. Specifically, Cystein-180 and Cystein-418 are primary responsible for the oligomerization process of HDC <ref name=xray/>.

Each monomer is divided into 3 structural domains: N-terminal (2-71), large domain (71-371), and small domain (372-477) (green link/figure 5) <ref name=jbc/>. A monomer is also composed of 49% helical structure and 13% beta sheet <ref name=4e10/>. One specifically long α-helix which span from Valine-359 to Arginine-393 connects the large and small domains together (Figure 2). Through hydrophobic effect, the N-terminal regions of the two monomers interact with each other extensively. At the same time, the large domains interact extensively due to electrostatic interactions. Thus, the N-terminal regions and large domains form the dimer interfaces of HDC <ref name=jbc/>.

<Structure load='4e1o' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

== Cofactor and Substrate Binding Pocket ==
[[Image:Histidine Decarboxylase Binding Site.png|thumb|right|Figure 3. Interactions between enzyme HDC and cofactor-substrate PLP-HME at the binding site <ref name=jbc/>.]]

The binding pocket for the cofactor PLP and the substrate histidine is located at the large domain. Since Histidine methyl ester (HME) is a substrate analog, PLP-HME can be utilized to demonstrate the binding interaction for the substrate-enzyme transition state at the active site <ref name=jbc/> <ref name=inhibition>PMID:850236</ref>. A one-dimensional representation of PLP-HME residing in the binding pocket can be seen in Figure 3. The hydrophobic pocket of the active site are produced by several hydrophobic amino acids including Trp-72, Tyr-80, Leu-102, Phe-104, Ala-275, Tyr-334, Ile-436 (Figure 3). This hydrophobic pocket allow for the substrate to be protected from the solvent during the catalytic reaction.

The residue Val-150, Ser-151, Asp-302, Val-305, Ser-354 and a water molecule are all involved in the numerous hydrogen bonding to the phosphate group of PLP (Figure 3). More importantly, Ser-354 is found to be a critical residue for the substrate-binding pocket of HDC <ref name=jbc/>. Other residues that are within the hydrogen bonding distance to the substrate includes Tyr-81, His-194, Thr-248, and Asp-273 (Figure 3). The imidazole ring N1 and carbonyl O of HME are held in place by the side chains of Tyr-81 and His-194 respectively whereas the O and N in the pyridine ring of PLP are held in place by the side chains of Thr-248 and Asp-273 (Figure 3).

A loop region appears between the residues 330 to 340 of the large domain <ref name=jbc/>. This loop protrudes from the large domain into the active site of another subunit of the dimer and makes up the entrance of the active site. Especially Tyr-334, which directly interacts with the backbone of Ser-195 through a fairly weak hydrogen bond <ref name=jbc/>. Due to the weak hydrogen bonding, the loop’s position is not rigidly fixed. Thus, this causes this loop to be fairly flexible enabling it to act as a gate to “open” or “close” the active site <ref name=jbc/>.

== Enzymatic Mechanism ==

During the catalytic reaction by HDC, the carboxyl group of L-histamine is removed with the help of cofactor pyridoxal-5'-phosphate (PLP) to generate the product histamine and byproduct carbon dioxide (CO2). The overall catalytic reaction is proposed to be a 1-step mechanism shown below <ref name=metabolism/> <ref name=uniprot/>:

[[Image:Histidine decarboxylase mechanism.svg.png|center]]

[[Image:Histidine decarboxylase 3D binding site.png|thumb|left|Figure 4. Structure of HDC dimer with PLP and HME. Subunit A is shown in blue, Subunit B is shown in green, and the PLP-HME is shown in orange <ref name=jbc/>.]]

The substrate L-histidine is proposed to enter from the gate constructed by 5 hydrophobic residues (Tyr-80, Phe-104, Tyr-334, Leu-335, and Leu-353) along with PLP <ref name=jbc/>. This gate is compose of a very flexible loop structure which “closes” upon the entering of the substrate. This phenomenon could be explained by the hydrophobic effect, which compacts the flexible hydrophobic entrance towards the hydrophobic binding site, thereby trapping the substrate inside the catalytic region. As shown in Figure 3, the ester group of HME is located immediate to the entrance. Since the hydrophobic gate separates the solvent from the methyl ester of HME, it appears to facilitate the conversion of carboxylate group to the less hydrophilic CO2 product during catalysis <ref name=jbc/>.

The substrate specificity of HDC mechanism involves the residue Ser-354. Due to the Van der Waal effect of its hydroxyl side chain, Ser-354 avoids other 6-membered ring amino acid such as tyrosine from entering the substrate binding pocket. With this specificity, Ser-354 only allow for the 5-membered ring histidine to be involved in the binding site during catalysis <ref name=jbc/>.

The numerous hydrogen bond interaction between the enzyme and PLP restrict the translation of the substrate or cofactor. In addition, the negative charges of phosphate group of PLP is stabilized by dipole moment from the neighboring N-terminus of the helix α5 seen in Figure 4 <ref name=jbc/>. These hydrogen bonding and stability effect assist in creating an environment for PLP to stay in place during the transitional state.

Additionally, the side chains of Thr-248 and Asp-273 are thought to be responsible for the protonation of the Oxide group and Nitrogen atom in the pyridine ring of PLP during the catalytic mechanism <ref name=jbc/>.

== References ==
{{reflist}}