Sandbox Reserved 773: Difference between revisions

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[[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/>

'''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 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/>.

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/>.

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== 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.

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/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/>.

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/>.

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/>.

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[[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 <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.

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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 ==

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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.

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==

Sandbox Reserved 773: Difference between revisions

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@@ Line 8: / Line 8: @@
 [[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/>
+'''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 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/>.
+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/>.
@@ Line 46: / Line 46: @@
 == 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.
+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/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/>.
+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/>.
-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' />
@@ Line 59: / Line 57: @@
 [[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 <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.
@@ Line 66: / Line 64: @@
 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 ==
@@ Line 81: / Line 78: @@
-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.
+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==