https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Andrea+GorrellProteopedia - User contributions [en]2026-09-18T14:11:56ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=User:Andrea_Gorrell/Sandbox_1&diff=1907513User:Andrea Gorrell/Sandbox 12014-03-28T22:53:25Z<p>Andrea Gorrell: </p>
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<div>==Adenylosuccinate Synthetase==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Andrea Gorrell/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
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== Function ==<br />
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== Disease ==<br />
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== Relevance ==<br />
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== Structural highlights ==<br />
Overview scene of the <scene name='58/581334/Overview/1'>dimer</scene> showing colors in rainbow.<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=User:Andrea_Gorrell/Sandbox_1&diff=1907512User:Andrea Gorrell/Sandbox 12014-03-28T22:47:23Z<p>Andrea Gorrell: New page: ==Adenylosuccinate Synthetase== <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> This is a default text for your page '''Andrea Gorrell/...</p>
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<div>==Adenylosuccinate Synthetase==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Andrea Gorrell/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=User:Andrea_Gorrell&diff=1907511User:Andrea Gorrell2014-03-28T22:46:40Z<p>Andrea Gorrell: </p>
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<div>[[User:Andrea Gorrell/Sandbox 1]]<br />
Assistant Professor at the University of Northern British Columbia<br />
<br />
PhD, Biochemistry (ISU)<br />
<br />
BSc, Biochemistry (Texas A&M)</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Cyanobacterial_BLUF&diff=1234965Cyanobacterial BLUF2011-04-26T22:24:54Z<p>Andrea Gorrell: New page: {{STRUCTURE_1x0p| PDB=1x0p | SCENE= }} __TOC__ =Introduction= The proteins containing sensors for blue light using [http://en.wikipedia.org/wiki/Flavin_adenine_dinucleotide FAD] (BLUF) dom...</p>
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<div>{{STRUCTURE_1x0p| PDB=1x0p | SCENE= }}<br />
__TOC__<br />
=Introduction=<br />
The proteins containing sensors for blue light using [http://en.wikipedia.org/wiki/Flavin_adenine_dinucleotide FAD] (BLUF) domains are one class of photoreceptor family that utilizes a flavin [http://en.wikipedia.org/wiki/Chromophore chromophore]<ref name ="one">PMID: 15876364</ref>. The other two classes include [http://en.wikipedia.org/wiki/Phototropin phototropins] (LOV) and [http://en.wikipedia.org/wiki/Cryptochrome cryptochromes]<ref name="two">PMID: 14730990</ref>. The BLUF domain was first discovered in [http://microbewiki.kenyon.edu/index.php/Rhodobacter ''Rhodobacter sphaeroides''] as the blue light photoreceptor involved in the repression of photosynthesis genes in AppA protein<ref name="one" /><ref name ="three">PMID: 12230978</ref>. The BLUF domain is known to exist in many bacteria, including cyanobacteria.<br />
<br />
One unique photosensing property of BLUF domain is a light induced spectral shift in the flavin absorption spectrum where the wavelength is longer by approximately 10nm<ref name="one" />. In AppA this shift occurs quickly upon illumination and is slowly reversed upon return to darkness. This spectral shift is not well understood and is not observed in other flavin binding photoreceptors. There have been two proposed models to explain the spectral shift observed in BLUF containing proteins: π-π stacking between the isoalloxazine ring of flavin and the phenol sidechain of a conserved tyrosine residue or protonation and deprotonation of the flavin ring coupled directly or indirectly with the conserved tyrosine residue<ref name ="four">PMID: 14556317</ref><ref name ="five">PMID: 15659451</ref>. These two models are based upon the conserved tyrosine residue Tyr9 in the T110078 protein.<br />
<br />
The BLUF domain can be divided into two categories: a multidomain protein, such as those found in the AppA from ''R. sphaeroides'', photoactivated adenylyl cyclase (PACα and PACβ) from [http://microbewiki.kenyon.edu/index.php/Euglena_gracilis ''Euglena gracilis''] and YcgF proteins of [http://en.wikipedia.org/wiki/Escherichia_coli ''Escherichia coli''], and a “short” protein composed of BLUF at the N-terminus<ref name ="six">PMID: 11875575</ref>. The amino acid sequences for each BLUF domain is unique, thus it is hard to discuss the role of the conserved tyrosine residue. The crystalline structure of the BLUF domain was solved using the “short” BLUF protein T110078 isolated from ''Thermosynechococcus elongatus'' BP-1<ref name="one" />. ''T. elongatus'' is a thermophyllic cyanobacteria with an optimum growth temperature near 57°C. Specifically, the T11078 protein is comprised of 143 amino acid residues and binds an oxidized FAD ligand non-covalently<ref name="one" />.<br />
<br />
=Structure=<br />
==Domains==<br />
[[Image:FADbonding.jpg|thumb|left|300px|Figure 1. The hydrogen bonds the FAD ligand forms with nearby amino acid residues.]]<br />
The BLUF domain is a <scene name='Sandbox_Reserved_310/Decamer/1'>decamer</scene> with a molecular weight of approximately 160kDa<ref name="one" />. There are ten monomers observed in each asymmetric unit. The crystalline structure of the BLUF domain from the T110078 protein was solved by single isomorphous replacement (SIR) method using a mercury derivative. The double ringed decamer has a diameter of approximately 95Å, a thickness of 60Å and a central channel approximately 35Å in diameter<ref name="one" />.<br />
Each monomer is comprised of 5 <scene name='Sandbox_Reserved_310/Monomer/3'>β-strands</scene> and 4<scene name='Sandbox_Reserved_310/Monomer/2'>α-helices</scene> in the order of β1α1β2β3α2β4β5α3α4. Specifically, the BLUF domain of the monomer contains β1α1β2β3α2β4β5, while the C-terminal domain contains α3α4<ref name="one" />. The C-terminal domain interacts with the end of the β-sheet of the neighbouring monomer.<br />
<br />
The isoalloxazine ring of FAD is located between <scene name='Sandbox_Reserved_310/Monomer/4'>α1 and α2</scene> of the BLUF domain, between two highly conserved hydrophobic residues: Ile24 and Ile66<ref name="one" />. FAD forms hydrogen bonds with the following amino acid residues: Asn21, Asn32, Gln50, Arg65 and Asp69 (Figure 1)<ref name="one" />. More specifically, the side chain of Asn31 binds to O2 of FAD and Asn32 binds to N3 and O4 of FAD. The guanido group of Arg65 contributes to a network between FAD and the apo protein. The amide N of the Gln50 sidechain interacts with N5 and O4 of FAD through hydrogen bonding, while the amide O of the sidechain is closely linked with the hydroxyl oxygen of the highly conserved Tyr8 residue, forming a FAD-Gln50-Tyr8 network<ref name="one" />. This conserved Tyr8 residue is the only residue that has been shown to be essential for light reaction in the BLUF domain containing AppA and Slr1694 proteins<ref name ="seven">PMID: 17042486</ref>.<br />
<br />
==Further Analyses==<br />
While Asn32, Gln50, Asp69, Arg71, His72 and Ser10 are completely conserved residues, Asn31, Arg65 and Ser28 are only moderately conserved. This network surrounding FAD is thought to be highly conserved in all BLUF domains. In order to study the importance of the interactions between the isoalloxaizine ring of FAD, and Asn31, Asn32 and Gln50, the amino acids were replaced with alanine residues<ref name="one" />. It was observed that the spectra of the mutants were qualitatively similar to that of the wild-type. However, the low energy absorbance peak of N32A (Asn32 replaced with Ala) was blue shifted compared to the wildtype by 6nm<ref name="one" />. This blue shift can be accounted for by the lack of hydrogen bonding between the side-chain and isoalloxazine ring<ref name="one" />. In the wild-type protein, Asn32 forms 2 hydrogen bonds with FAD; the absence of these bonds allows relocation of an electron on FAD, resulting on the spectral blue shift.<br />
<br />
The Q40A mutant showed very little spectral changes during illumination. These results suggest that Gln50 is critical for light reaction in BLUF domains and is thus totally conserved<ref name="one" />. Transient bleaching of flavin was observed instead of red-shifting; this suggests that light excitation of flavin in Q50A resulted in photoreduction of flavin<ref name="one" />. In general, a free flavin in solution is sequentially reduced with two electrons upon exposure to light. The first electron reduces the double bond at N5 and the second electron reduces at N1 of the isoalloxazine ring. In BLUF proteins, the role of Gln50 may be to prevent the initial photoreduction at N5 and allow a reaction leading to the spectral shift to a longer wavelength. This may be achieved by the hydrogen bonding between the amide N of Gln50 and the N5 of the isoalloxazine ring of FAD.<br />
<br />
Similar hydrogen bonding networks surrounding the isoalloxazine ring are found in other light sensing proteins such as the LOV proteins<ref name="one" />. The most critical residue in the flavin sensor proteins appears to be the one that interacts closely with N5 of the isoalloxazine ring<ref name="one" />.<br />
<br />
=Function=<br />
Overall, the main function of the BLUF domain is to detect and respond to blue light. More specifically, in ''R. sphaeroides'', the BLUF domain is a blue light photo receptor involved in repressing the photosynthesis genes at the N-terminal region of the AppA protein<ref name="three" />. In ''E. gracilis'', the BLUF domain of PAC complexes serves as a blue light receptor in photophobic responses<ref name="six" />. <br />
<br />
=References=<br />
<references /><br />
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This page originally authored by Amanda Cookhouse</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Heme_oxygenase&diff=1234959Heme oxygenase2011-04-26T22:22:02Z<p>Andrea Gorrell: New page: {{STRUCTURE_2dy5| PDB=2dy5 | SCENE=Sandbox_Reserved_308/Heme_oxygenase_transparent/2 }} __TOC__ ==='''General Information'''=== ---- Heme Oxygenase (HO) is a member of the Hemoprotei...</p>
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<div><br />
{{STRUCTURE_2dy5| PDB=2dy5 | SCENE=Sandbox_Reserved_308/Heme_oxygenase_transparent/2 }}<br />
__TOC__<br />
==='''General Information'''===<br />
----<br />
<br />
Heme Oxygenase (HO) is a member of the Hemoprotein family and catalyzes the Oxygen-dependent cleavage of the porphyrin ring of heme, using reducing equivalents like NADH to produce biliverdin, iron and CO <ref name="HO">PMID:17253780</ref>. HO consists of two main isoforms which are present in mammals, HO-1 and HO-2. The two isoforms are products of different genes, are different molecular sizes (32 kDa and 36 kDa respectively) and contain a different primary structure showing only 58% homology <ref name="HO1">PMID:15522396</ref>. However studies have shown that the two isoforms share a region with 100% secondary structure homology which is believed to be the catalytic site of the protein<ref name="HO"/>. The heme oxygenase isoforms are not free throughout the body but sequestered to certain tissues. The Heme oxygenase -1 is strongly expressed in the spleen and liver whereas Heme Oxygenase-2 is strongly expressed in the brain, testis and vascular systems<ref name="sc1">PMID:12909459</ref>.<br />
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==='''Ligand'''===<br />
----<br />
HO non-covalently binds to a ligand known as a heme group more specifically Heme B. This Heme is the most abundant heme group commonly recognized for its role in oxygen transport and storage within mammalian tissues <ref name="heme">PMID:170266</ref>. This group is contains a large heterocyclic ring known as a porphyrin ring with an iron atom in the center. The center iron atom serves as a source of electrons for the redox reaction to occur <ref name="heme"/>. However this group is susceptible to damage from many stressors including physical shock and therefore needs to be broken down or recycled when theses stressors occur <ref name="HO"/>. <br />
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==='''Structure'''===<br />
----<br />
<Structure load='2dy5' size='350' frame='true' align='left' caption='Heme Oxygenase' /><br />
<br />
HO is a 233 residue protein with a secondary structure consisting of <scene name='Sandbox_Reserved_308/7_helces/1'> seven α-helices </scene> which interacts with a <scene name='Sandbox_Reserved_308/Heme_group/1'> heme group </scene> <ref name="HO"/> at the optimum pH of 7.4; at 37 degrees C <ref name="PH">PMID:2158889</ref>. The heme is sandwiched between two helices termed the <scene name='Sandbox_Reserved_308/Prox_dis/1'> proximal and distal helices </scene> <ref name="HO3">PMID:18798608</ref>. The proximal helix provides the His 25 heme ligand along with the various contact residues (Ala 28 and Glu 29), but also Thr 21 which contacts the heme through a water molecule <ref name="HO"/>. On the distal side where the ligands binds (the catalytic site) there is a highly conserved sequence of Glycine residues (<scene name='Sandbox_Reserved_308/Test/4'>Gly 139, Gly 143-144</scene>) that provide a required flexibility for the reaction to occur <ref name="HO"/>. This results in the backbone atoms of Gly 139 and Gly 143 to directly contact the heme. Inhibition of HO is provided by compounds such as imidazole-dioxolane which disrupt this flexibility, thereby forcing the HO protein to become rigid, stopping its function <ref name="sc2">PMID:3290025</ref>. <br />
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Of the four meso edges of the heme only one remains exposed (<scene name='Sandbox_Reserved_308/Heme_group/2'>α-meso edge</scene>) while the rest remain buried in the protein <ref name="HO1"/>. The exposed edge is the target of the HO reaction and requires the correct orientation for the hydroxylation reaction to occur<ref name="HO3"/>. This orientation is aided by the charges associated with the <scene name='Sandbox_Reserved_308/Heme_group/3'> propionate residues </scene> on the heme. The residues of <scene name='Sandbox_Reserved_308/Propintaes_with_residues/1'> Lys 179, Arg 183, Lys 18 Lys 22 and Tyr 134 </scene> are all near the propionates to anchor it via non convalent bonds so the a-meso carbon is in position for the hydroxylation reaction<ref name="sc3">PMID:11875494</ref>. The propinates are located on the opposite side as the α-meso edge. The vinyl and methyl heme substituents do not appear to be important in orienting the heme due to the fact that they may be disordered about the y- axis which would change only the location of the methyl and vinyl groups while retaining the position of the propionates and the a-meso edge <ref name="sc3"/>. .<br />
<br />
==='''Function'''===<br />
----<br />
<br />
[[Image:Heme_Oxygenase_Reaction.JPG|350px|thumb|right|Figure 1: Heme oxygenase reaction converting Heme to Billiverdin]] <br />
<br />
Heme Oxygenase has two main functions, firstly it recycles iron supplies within the cell to maintain homeostasis and secondly it produces a product (biliverdin) that can be converted to a powerful antioxidant (bilirubin) which can aid in preventing oxidative cell damage <ref name="HO3"/>. The overall reaction consists of three sequential oxidation steps. In the first step the Oxygen bound to the heme iron is activated to become hydroperoxide. The production of α-hydroxyheme is accomplished by the electrophilic addition of its terminal oxygen to the α-meso carbon <ref name="HO3"/>. Then Heme Oxygenase converts α-hydroxyheme to verdoheme with the removal of the CO at the α-meso carbon (approximately 85% of CO produced under normal conditions is from this reaction)<ref name="HO3"/>. Lastly, the oxygen bridge of verdoheme is cleaved to produce biliverdin-iron chelate before the dissociation of the iron to biliverdin. (Figure 1) The electrons required for catalytic turnover of the enzyme are provided, in mammalian systems, by NADPH-cytochrome P450 reductase<ref name="HO3"/>. Studies suggest that the CO produced by the heme oxygenase reaction also functions to have anti-inflammatory, anti-proliferative and anti-apoptotic effects <ref name="sc2"/> to prevent cell damaage.<br />
<br />
A classic example of this reaction is a bruise. When tissue obtains a hard hit the erythrocytes release the heme creating a <font color='red'>Red</font> color. The heme then gets converted to biliverdin via heme oxygenase to produce a <font color='green'>green</font> color. Finally the conversion of biliverdin to bilirubin displays a <font color='gold'>yellow</font> color. Therefore the reaction can be visibly observed <ref name="HO5">PMID:18487208</ref>.. <br />
<br />
<br />
==='''Medical Significance and Future Implications'''===<br />
----<br />
[[Image:Heme_Oxygenase_attack.JPG|250px|thumb|left|Figure 2: Neutralizing oxidant attack with antioxidants produced through the heme oxygenase reaction]] <br />
The lungs are a major target for various inflammatory, oxidative, carcinogenic and infectious pressures, which have the ability to result in a range of lung diseases like chronic obstructive lung diseases (COLD)<ref name="HO6">PMID:20704548</ref>. The Induction of HO-1 is a crucial defense mechanism during these acute and chronic lung processes. The defense is obtained from the anti-oxidant, anti-inflammatory and anti-apoptotic properties of the products formed from the HO reaction <ref name="HO6"/>. (Figure 2) Therefore manipulation of the HO reaction and HO can have immense therapeutic potential against a range of lung diseases, if optimal levels of incorporation can be achieved. <br />
<br />
The products of the HO reaction are not just beneficial for lung diseases but also have a cytoprotective effect through the p38-MAPK pathway, and are a potential therapeutic treatment in cancer<ref name="HO"/>. Recent studies have also shown that inhibition of the HO-1 reduces Kaposi sarcoma tumor growth <ref name="HO"/>. Therefore future implications on regulating and manipulating this protein can have a massive impact on medical treatments.<br />
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==Additional Resources==<br />
For additional information, See: [[Cancer]] <br /><br />
For additional information, See: [[NADPH Cytochrome P450 Oxidoreductase]] <br /><br />
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==References==<br />
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<references/><br />
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This page originally authored by Barinder Chahal</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=ModG&diff=1234954ModG2011-04-26T22:19:01Z<p>Andrea Gorrell: New page: {{STRUCTURE_1h9j| PDB=1h9j | SCENE= }} __TOC__ =Introduction to ModG= ModG is a cytoplasmic molybdate-binding protein exclusive to the aerobic nitrogen-fixer ''Azobacter vinelandii''.<ref...</p>
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<div>{{STRUCTURE_1h9j| PDB=1h9j | SCENE= }}<br />
__TOC__<br />
<br />
=Introduction to ModG=<br />
ModG is a cytoplasmic molybdate-binding protein exclusive to the aerobic nitrogen-fixer ''Azobacter vinelandii''.<ref name="MODGR1">PMID:11352591</ref> Molybdate is a molybdenum oxyanion (MoO42-). The group 6 element molybdenum is required by many enzymes that catalyze reactions associated with carbon, nitrogen, or sulfur metabolism.<ref name="MODGR2">PMID:21454640</ref> It is also part of the cofactor of the molybdoenzyme ModG. Not surprisingly, studies have linked ModG to molybdenum homeostasis within the cell.<ref name="MODGR1"/><br />
<br />
=Structure=<br />
<Structure load= size='300' frame='true' align='left' caption='Unbound ModG' scene = 'Sandbox_Reserved_306/1h9j/3' /><br />
The molybdoenzyme is a homotrimer.<ref name="MODGR1"/> It can bind up to 8 molybdate molecules between 4 different types of <scene name='Sandbox_Reserved_306/1h9j/4'>active sites</scene> on subunit interfaces (BS1, BS1’, BS2, and BS2’). Binding site 1 and binding site 2 are found at opposite ends of the protein; binding site 1’ and binding site 2’ are found off-axis near like ends.<ref name="MODGR3">PMID:9862806</ref> The sites are connected by hydrogen bonds and thus a cooperative binding mechanism has been proposed for ModG whereby ligand engagement with type 2 sites induces conformational changes to asparagine residues at type 1 sites, reading the site for ligand interactions.<ref name="MODGR4">PMID:7665518</ref> The structure of ModG was solved by Delarbe et al. using multi-wavelength anomalous dispersion (MAD).<ref name="MODGR5"/> Crystallization required salt-free conditions established with polyethylene glycol (PEG), at which point the authors solved the PEG crystal form using molecular replacement.<ref name="MODGR5"/><br />
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The protein is made up of 3 identical subunits that have 67 amino acid pairs and are 14.3 kDa in size.<ref name="MODGR1"/> In trimer form the subunits are perpendicular to each other and intersect at the 3-fold axis (as seen in the crystallized form).<ref name="MODGR3"/> Each subunit is composed of two β-barrel domains (Domain I and Domain II) that each feature a short 310-helix.<ref name="MODGR3"/> Each β-barrel domain includes five antiparallel β-strands arranged in a <scene name='Sandbox_Reserved_306/1h9j/7'>Greek Key</scene> motif that is capped by two-turn α-helices.<ref name="MODGR3"/> The folding arrangement of the ModG domains is that of an oligomer-binding (OB) fold, characteristic of toxins and other intracellular oxyanion-binding proteins.<ref name="MODGR3"/> In trimerization, N and C termini (both found in Domain I) of a subunit interact with the β5-β6 loop (Domain II) of the adjoining subunit by sharing antiparallel β-sheets. Approximately 40% of monomer surface area is buried when the protein is in trimer form.<ref name="MODGR1"/><br />
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<br />
<br />
=Properties and binding affinity=<br />
About 60% of each subunit interface is <scene name='Sandbox_Reserved_306/1h9j/8'>non-polar</scene> (40% is polar); furthermore, there is an unequal charge distribution that is attributed to the presence of 4 side chains.<ref name="MODGR2"/><ref name="MODGR4"/> These include: Lys60, Lys132, Arg6, and Arg78.<ref name="MODGR1"/> The <scene name='Sandbox_Reserved_306/1h9j/10'>lysine residues</scene> are both found on the type 2 binding sites and are entirely buried in the protein; the <scene name='Sandbox_Reserved_306/1h9j/5'>arginine residues</scene> are partly exposed.<ref name="MODGR1"/> This leaves the interface particularly electropositive; electrostatic repulsion is balanced by several favorable interactions that include the formation of 24 hydrogen bonds, 2 salt bridges and approximately 24% of total hydrophobic surface buried (per subunit).<ref name="MODGR4"/> The trimer is further stabilized by the binding of an oxyanion which would have a neutralizing effect.<ref name="MODGR3"/><br />
<br />
Type 1 binding sites utilize hydrogen bonds and interactions with uncharged polar residues to bind molybdate.<ref name="MODGR4"/> The tight pocket volume and rigidity of the site suggest that there is high selectivity for molybdate (or tungstate because ModG cannot differentiate between the two oxyanions).<ref name="MODGR4"/> Type 2 sites are comparatively larger in pocket volume, supple, and feature electropositive lysine residues that would contribute to high affinity for negatively charged oxyanions like molybdate.<ref name="MODGR4"/> Because the type 2 sites are larger and more flexible, there would be less specificity for molybdate and thus other oxyanions such as phosphate would likely compete for binding.<ref name="MODGR3"/><ref name="MODGR4"/><br />
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<br />
=Function in Bacteria=<br />
The ability of ''A. vinelandii'' to differentiate between molybdate and other oxyanions is of particular interest to researchers.<ref name="MODGR1"/><ref name="MODGR2"/><ref name="MODGR5"/> Phosphate is distinguished from molybdate by the divergence in protonation states: phosphate is protonated at physiological pH whereas molybdate is not.<ref name="MODGR2"/> The distinction between sulfate and molybdate is reliant upon differences in ligand size.<ref name="MODGR2"/> Interestingly, molybdate permeases are not able to distinguish between tungstate and molybdate.<ref name="MODGR1"/><ref name="MODGR2"/> Regulation of these intracellular metabolites is attributed to other molybdate-binding proteins collectively known as molbindins.<ref name="MODGR1"/><ref name="MODGR5">PMID:10393312</ref><br />
<br />
<br />
=Fate=<br />
ModG is eventually degraded and incorporated into molybdopterin, a cofactor of molybdenum enzymes, or the iron-molybdenum cofactor of a nitrogenase enzyme.<ref name="MODGR1"/><ref name="MODGR2"/> Currently there is little known about cofactor biosynthesis involving the ModG protein.<ref name="MODGR1"/><br />
<br />
=References=<br />
<references/><br />
<br />
<br />
=See also=<br />
[[Category:Molybdenum-containing enzyme]]<br />
<br />
This page originally authored by Corbin Black</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Ribose-5-phosphate_isomerase&diff=1234951Ribose-5-phosphate isomerase2011-04-26T22:17:13Z<p>Andrea Gorrell: New page: {{STRUCTURE_3enw| PDB=3enw | SCENE= }} __TOC__ Ribose 5-phosphate isomerase (Rpi) is a highly conserved protein that acts as an enzyme in both eukaryotic and prokaryotic metabolic path...</p>
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<div>{{STRUCTURE_3enw| PDB=3enw | SCENE= }}<br />
__TOC__<br />
<br />
Ribose 5-phosphate isomerase (Rpi) is a highly conserved protein that acts as an enzyme in both eukaryotic and prokaryotic metabolic pathways<ref name="rpi">PMID:12517338</ref>. Specifically, Rpi catalyzes the reaction that converts <scene name='Sandbox_Reserved_305/Ligand/1'> ribose-5-phosphate </scene> (R5P) to ribulose-5-phosphate (Ru5P). Rpi exists as two distinct protein forms known as RpiA and RpiB, both of which catalyze the same reaction, and most organisms express one or both of these enzymes.<br />
The functional and structural properties of RpiA have been determined from organisms including ''Escherichia coli, Pyrococcus horikoshii, Saccharomyces cerevisiae,'' among others<ref name="rpi">PMID:12517338</ref>. These studies have revealed an important role RpiA plays in the Calvin cycle in plants and pentose phosphate pathway in both plants and animals <ref name="rpi2">PMID:19214439</ref>. The sequence conservation among RpiA subfamilies also shows the considerable evolutionary significance in preserving its function across different organisms.<br />
<br />
==Function==<br />
===Pentose Phosphate Pathway=== <br />
The pentose phosphate pathway is comprised of two separate pathways, the oxidative and non-oxidative paths. In the non-oxidative pathway RpiA converts Ru5P to R5P, subsequently the ribulose phosphate 3-epimerase converts the R5P to xylulose-5-phosphate<ref name="rpi2">PMID:19214439</ref>. The pentose phosphate pathway is a major source of NADPH, which is necessary for the removal of oxidants within cells<ref name="rpi">PMID:12517338</ref>.<br />
[[Image:pppo.png|thumb|right|Figure 1: Non-oxidative pentose phosphate pathway]]<br />
<br />
===Calvin Cycle===<br />
The Calvin Cycle converts carbon dioxide and water into carbohydrates which can be utilized by the organism. RpiA plays an important role in the cycle, converting ribose-5-phosphate to ribulose-5-phosphate, which is subsequently converted to ribulose 1,5,-biphosphate (RuBP). RuBP is further reacted to form glyeraldhyde-3-phosphate, which is a precursor to the formation of larger carbohydrates<ref name="rpi">PMID:12517338</ref>.<br />
<br />
==Structure==<br />
<Structure load='3enw' size='280' frame='true' align='left' caption='Insert caption here' scene='Insert optional scene name here' /><br />
The structure of RpiA has been identified in many organisms including ''E. coli'' and ''Vibrio vulnificus''. The crystallized RpiA structure from both of these organisms is highly conserved in many respects. RpiA exists as a dimer with pseudo-2-fold symmetry, the interface of the dimer is composed of six different segments, which contain a number of interactions occurring between <scene name='Sandbox_Reserved_305/Alpha_helices/2'> α-helices </scene> and <scene name='Sandbox_Reserved_305/Beta_sheets/1'> β-sheets </scene>. Two salt bridges also link <scene name='Sandbox_Reserved_305/104_and_183_no_ssbond/1'> Lys104 and Glu183 </scene> of the same subunit. The <scene name='Sandbox_Reserved_305/Activesite/3'>RpiA and R5P complex</scene> occurs through the interaction between the ligand (R5P) and the following residues in the RpiA: <scene name='Sandbox_Reserved_305/Test/1'>Gly97, Asp84</scene>, Lys121, Lys7, Thr31 and Ser30. RpiA contains two sites for this interaction allowing two R5Ps to interact with one RpiA. The VvRpiA-R5P complex resembles the ''E. coli'' RpiA-A5P complex; however the VvRpiA-A5P complex reveals a different position than the R5P binding mode. The A5P interacts with the following residues: Asp8, Lys7, Ser30, Asp118 and Lys121.<br />
<br />
==Medical and Future Implications==<br />
<br />
Ribose-5-Phosphate Isomerase deficiency has been associated with the progression of leukoencephalopathy <ref name="rpi3">PMID:14988808</ref>. Leukoencephalopathy is a disorder associated with the deterioration of white-matter in brain tissue, and individuals with this diseases exhibit neurological deficits, such as psycho-motor retardation<ref name="rpi3">PMID:14988808</ref>. A study performed by Huck and colleagues, revealed the Rpi gene-sequence of having a frameshift and missense mutation, which led to a defect in the pentose-phosphate pathway, which was prevalent in patients suffering from leukoencephalopathy<ref name="rpi3">PMID:14988808</ref>.<br />
[[Image:rpi.png|thumb|right|Figure 2: Ribose-5-Phosphate Isomerase A]]<br />
In a study done by Becker and colleagues, RpiA was shown to play an important role in the pathogenesis of the malarial parasite, ''Plasmodium falciparum'', which is one of the species of ''Plasmodium''that causes malaria in humans<ref name="rpi4">PMID:16339145</ref>. The RpiA specifically supplies the increased requirement of R5P required by Plasmodium cells that use the R5P to generate 5-phospho-D-ribose-a-1-pyrophosphate (PRPP) needed for nucleic acid synthesis<ref name="rpi4">PMID:16339145</ref>. <br />
<br />
A major issue in agriculture is related to the overuse of antibiotics. In recent history there has been an increase in scientific data showing the direct relationship between the overuse of antibiotics in the agricultural industry, resulting in the cultivation and spread of antibiotic-resistant bacteria. A large number of bacteria presenting abnormal symptoms in infected organisms results from unbalanced cellular ribose levels, and a proposed treatment for this type of infection is creating inhibitors that target RpiA, which would have adverse affects on the pathogenic bacteria<ref name="rpi5">PMID:9371327</ref>.<br />
<br />
Ribose 5-Phosphate Isomerase plays a huge role in producing nucleotides and cofactors from ribose 5-phosphate in the pentose phosphate pathway and calvin cycle. Since this enzyme plays a major role in both eukaryotic and prokaryotic organisms it is a valuable enzyme and implies that RpiA subfamilies have a significant evolutionary origin<ref name="rpi6">PMID:19214439</ref>.<br />
<br />
<br />
<br />
==References==<br />
<references/><br />
<br />
This page originally authored by Jasmeet Bhullar</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Coenzyme_A-Disulfide_Reductase&diff=1234948Coenzyme A-Disulfide Reductase2011-04-26T22:14:19Z<p>Andrea Gorrell: </p>
<hr />
<div>{{STRUCTURE_3cge| PDB=3cge | SCENE=Sandbox_Reserved_304/Casual_scene/1}}<br />
__TOC__<br />
==General Information==<br />
Coenzyme A (CoASH) replaces glutathione as the major low-molecular weight thiol in [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] it is maintained in the reduced state by coenzyme A-disulfide reductase (CoADR), a homodimeric enzyme similar to NADH peroxidase, but containing a novel Cys43-SSCoA redox center.<ref name="0exia">PMID:16981688</ref> <br />
<br />
Coenzyme A-Disulfide Reductase, is an enzyme that is proposed to be involved in the robust oxygen-defense systems of aerobic and facultatively anaerobic organisms. <ref name="1exia">PMID:15720393</ref><br />
<br />
The maintenance of low intracellular levels of cysteine in organisms has been attributed to the avoidance of the hydrogen peroxide produced during the rapid O2-dependent oxidation to cystine, necessitating the use of other small molecular mass thiols such as glutathione for the maintenance of internal redox levels. The results presented above are consistent with a role for CoA in maintaining a reducing environment or serving as a pool of reducing equivalents at the very high temperatures and high concentrations of metals found in the natural environment of 'Pyrococcus' one of the bacteria CoADR is involved with. The pyrococcal CoADR described in this work is able to efficiently utilize both NADPH and NADH, a result which is consistent with the unusual utilization of reduced nucleotide coenzymes by Pyrococcus. The central metabolism of this organism uses an unusual NADPH-dependent sulfide dehydrogenase which is capable of both the NADPH-dependent reduction of elemental sulfur and the NADP+-dependent oxidation of ferredoxin. <ref name=1exia/><br />
<br />
phCoADR is stable for months at both −80 °C and −20 °C, and has half-lives of > 100 and 39 h at 85° and 95 °C, respectively. <ref name="1exia"/><br />
<br />
==Structure==<br />
<applet load='3cge' size='290' color='black' frame='true' align='left' scene='Sandbox_Reserved_304/Casual_scene/1' caption='Figure 1: Highlighting the chains and associated ligands of CoADR'/><br />
<scene name='Sandbox_Reserved_304/Casual_scene/1'>CoADR</scene> is a complex, multidomain protein composed of two chains, (<scene name='Sandbox_Reserved_304/Chain_a/1'>A</scene>,<scene name='Sandbox_Reserved_304/Chain_b/2'>B</scene>). It also has three different types of associated ligands; two <scene name='Sandbox_Reserved_304/Coa/2'>CoA</scene>, two <scene name='Sandbox_Reserved_304/Ndp/2'>NDP</scene> and two <scene name='Sandbox_Reserved_304/Fad/3'>FAD</scene> <br />
<br />
CoADR's ligands have been shown to follow four conserved sequence motifs. Among the four conserved sequence motifs identified by Dym and Eisenberg as being shared by all NAD(P)H-dependent members of the GR1 subfamily [which includes all of the PNDOR enzymes], one represents part of the βαβ Rossmann NAD(P)H dinucleotide-binding motif (<scene name='Sandbox_Reserved_304/Beta_sheets/2'>Beta Sheets</scene>). This specific motif has most recently been applied in the description and functional analysis of the “two dinucleotide binding domains” flavoproteins superfamily containing both FAD- and NAD(P)H-binding motifs.<ref name="2exia">PMID:18399646 </ref><br />
<br />
The crystal structure of CoADR reveals one symmetrical dimer (chains A and B) in the asymmetric unit, consistent with the quaternary structures observed with nearly all PNDOR enzymes. Both polypeptide chains are clearly defined in the electron density and have similar average B-factors of 17 Å2 and 18 Å2, respectively. Less well-defined regions of the protein involve two different segments with solvent-exposed loops, residues 51–61 in chain A with an average B-factor of 34 Å2 and residues 361–378 in chain B with an average B-factor of 24 Å2.<ref name="2exia"/><ref name="1exia"/> These two regions are better ordered in the corresponding complementary subunits with average B-factors of 21 Å2 and 14 Å2, respectively, owing in large part to crystal contacts with symmetry mates. These variations are therefore attributed to different crystal-packing environments rather than to intrinsic structural differences between the A and B chains. The CoADR monomer consists of three domains, the two-part FAD-binding domain (residues 1–114 and 242–319), the NADPH-binding domain (residues 115–241), and the C-terminal Interface domain (residues 323–438). As recently analyzed, this subfamily includes functionally diverse proteins such as glutamate synthase, adrenodoxin reductase, and cyclohexanone monooxygenase. <ref name="2exia"/><br />
<br />
The FAD- and NADPH-binding domains of CoADR both have canonical Rossmann folds ; each consists of a central five-stranded parallel β-sheet, with a three-stranded antiparallel β-sheet packed on one side of the central sheet and several α-helices on the opposite side. CoAS- is associated with a cleft at the dimer interface; this cleft is formed by portions of the FAD-binding domain of chain A and the Interface domain of chain B, which contains a large five-stranded antiparallel β-sheet with three short α-helices at the C-terminus.<ref name="2exia"/><br />
<br />
<br />
==Medical Application==<br />
The human pathogen Staphylococcus aureus does not utilize the thiol/disulfide redox system based on glutathione and glutathione reductase (GSR)1 found in eukaryotes and Gram-negative bacteria. Instead, S. aureus appears to use a redox system based on CoA and coenzyme A disulfide reductase (CoADR) CoADR is a dimeric flavoprotein that specifically catalyzes the NADPH dependent reduction of oxidized CoA thereby contributing to the high ratio of CoA/oxidized CoA (<450) and the intracellular reducing environment. <ref name="3exia">PMID:9488708 </ref><br />
Additionally, the disparate disulfide specificities of CoADR and its presumed human counterpart, GSR, identified this enzyme as a possible target for the design of selective inhibitors that would interrupt the thiol metabolism of 'S. aureus' and function as anti-staphylococcal agents.<ref name="3exia"><br />
<br />
<br />
==Recent News==<br />
Very recently, Ojha et al. have classified coenzyme A-disulfide reductase (CoADR) as one of the prototype enzymes of the NADH Peroxidase/Oxidase and CoAD Reductase (POR) subgroup [also previously identified as Group 3 of the PNDOR family] of the “two dinucleotide binding domains” flavoproteins superfamily. A critical distinction between CoADR and all other PNDOR enzymes, including the Group 1 and Group 2 enzymes, lies in the fact that CoADR is the only disulfide reductase that uses a single active-site Cys in catalysis . The recent crystal structure for Staphylococcus aureus CoADR [SACoADR] revealed the resting state of the enzyme as containing a mixed disulfide of this Cys (SACoADR Cys43) with CoASH; this nonflavin redox center plays an essential role in catalysis. The structure also identified two Tyr residues in the active site, Tyr361′ and Tyr419′, that were proposed to be important in catalysis. <ref name="2exia">PMID:18399646 </ref><br />
<br />
<br />
=References=<br />
<references/><br />
Page originally authored by David Biel</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Coenzyme_A-Disulfide_Reductase&diff=1234947Coenzyme A-Disulfide Reductase2011-04-26T22:13:57Z<p>Andrea Gorrell: New page: {{STRUCTURE_3cge| PDB=3cge | SCENE=Sandbox_Reserved_304/Casual_scene/1}} =Coenzyme A-Disulfide Reductase= __TOC__ ==General Information== Coenzyme A (CoASH) replaces glutathione as the ma...</p>
<hr />
<div>{{STRUCTURE_3cge| PDB=3cge | SCENE=Sandbox_Reserved_304/Casual_scene/1}}<br />
=Coenzyme A-Disulfide Reductase=<br />
<br />
__TOC__<br />
==General Information==<br />
Coenzyme A (CoASH) replaces glutathione as the major low-molecular weight thiol in [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] it is maintained in the reduced state by coenzyme A-disulfide reductase (CoADR), a homodimeric enzyme similar to NADH peroxidase, but containing a novel Cys43-SSCoA redox center.<ref name="0exia">PMID:16981688</ref> <br />
<br />
Coenzyme A-Disulfide Reductase, is an enzyme that is proposed to be involved in the robust oxygen-defense systems of aerobic and facultatively anaerobic organisms. <ref name="1exia">PMID:15720393</ref><br />
<br />
The maintenance of low intracellular levels of cysteine in organisms has been attributed to the avoidance of the hydrogen peroxide produced during the rapid O2-dependent oxidation to cystine, necessitating the use of other small molecular mass thiols such as glutathione for the maintenance of internal redox levels. The results presented above are consistent with a role for CoA in maintaining a reducing environment or serving as a pool of reducing equivalents at the very high temperatures and high concentrations of metals found in the natural environment of 'Pyrococcus' one of the bacteria CoADR is involved with. The pyrococcal CoADR described in this work is able to efficiently utilize both NADPH and NADH, a result which is consistent with the unusual utilization of reduced nucleotide coenzymes by Pyrococcus. The central metabolism of this organism uses an unusual NADPH-dependent sulfide dehydrogenase which is capable of both the NADPH-dependent reduction of elemental sulfur and the NADP+-dependent oxidation of ferredoxin. <ref name=1exia/><br />
<br />
phCoADR is stable for months at both −80 °C and −20 °C, and has half-lives of > 100 and 39 h at 85° and 95 °C, respectively. <ref name="1exia"/><br />
<br />
==Structure==<br />
<applet load='3cge' size='290' color='black' frame='true' align='left' scene='Sandbox_Reserved_304/Casual_scene/1' caption='Figure 1: Highlighting the chains and associated ligands of CoADR'/><br />
<scene name='Sandbox_Reserved_304/Casual_scene/1'>CoADR</scene> is a complex, multidomain protein composed of two chains, (<scene name='Sandbox_Reserved_304/Chain_a/1'>A</scene>,<scene name='Sandbox_Reserved_304/Chain_b/2'>B</scene>). It also has three different types of associated ligands; two <scene name='Sandbox_Reserved_304/Coa/2'>CoA</scene>, two <scene name='Sandbox_Reserved_304/Ndp/2'>NDP</scene> and two <scene name='Sandbox_Reserved_304/Fad/3'>FAD</scene> <br />
<br />
CoADR's ligands have been shown to follow four conserved sequence motifs. Among the four conserved sequence motifs identified by Dym and Eisenberg as being shared by all NAD(P)H-dependent members of the GR1 subfamily [which includes all of the PNDOR enzymes], one represents part of the βαβ Rossmann NAD(P)H dinucleotide-binding motif (<scene name='Sandbox_Reserved_304/Beta_sheets/2'>Beta Sheets</scene>). This specific motif has most recently been applied in the description and functional analysis of the “two dinucleotide binding domains” flavoproteins superfamily containing both FAD- and NAD(P)H-binding motifs.<ref name="2exia">PMID:18399646 </ref><br />
<br />
The crystal structure of CoADR reveals one symmetrical dimer (chains A and B) in the asymmetric unit, consistent with the quaternary structures observed with nearly all PNDOR enzymes. Both polypeptide chains are clearly defined in the electron density and have similar average B-factors of 17 Å2 and 18 Å2, respectively. Less well-defined regions of the protein involve two different segments with solvent-exposed loops, residues 51–61 in chain A with an average B-factor of 34 Å2 and residues 361–378 in chain B with an average B-factor of 24 Å2.<ref name="2exia"/><ref name="1exia"/> These two regions are better ordered in the corresponding complementary subunits with average B-factors of 21 Å2 and 14 Å2, respectively, owing in large part to crystal contacts with symmetry mates. These variations are therefore attributed to different crystal-packing environments rather than to intrinsic structural differences between the A and B chains. The CoADR monomer consists of three domains, the two-part FAD-binding domain (residues 1–114 and 242–319), the NADPH-binding domain (residues 115–241), and the C-terminal Interface domain (residues 323–438). As recently analyzed, this subfamily includes functionally diverse proteins such as glutamate synthase, adrenodoxin reductase, and cyclohexanone monooxygenase. <ref name="2exia"/><br />
<br />
The FAD- and NADPH-binding domains of CoADR both have canonical Rossmann folds ; each consists of a central five-stranded parallel β-sheet, with a three-stranded antiparallel β-sheet packed on one side of the central sheet and several α-helices on the opposite side. CoAS- is associated with a cleft at the dimer interface; this cleft is formed by portions of the FAD-binding domain of chain A and the Interface domain of chain B, which contains a large five-stranded antiparallel β-sheet with three short α-helices at the C-terminus.<ref name="2exia"/><br />
<br />
<br />
==Medical Application==<br />
The human pathogen Staphylococcus aureus does not utilize the thiol/disulfide redox system based on glutathione and glutathione reductase (GSR)1 found in eukaryotes and Gram-negative bacteria. Instead, S. aureus appears to use a redox system based on CoA and coenzyme A disulfide reductase (CoADR) CoADR is a dimeric flavoprotein that specifically catalyzes the NADPH dependent reduction of oxidized CoA thereby contributing to the high ratio of CoA/oxidized CoA (<450) and the intracellular reducing environment. <ref name="3exia">PMID:9488708 </ref><br />
Additionally, the disparate disulfide specificities of CoADR and its presumed human counterpart, GSR, identified this enzyme as a possible target for the design of selective inhibitors that would interrupt the thiol metabolism of 'S. aureus' and function as anti-staphylococcal agents.<ref name="3exia"><br />
<br />
<br />
==Recent News==<br />
Very recently, Ojha et al. have classified coenzyme A-disulfide reductase (CoADR) as one of the prototype enzymes of the NADH Peroxidase/Oxidase and CoAD Reductase (POR) subgroup [also previously identified as Group 3 of the PNDOR family] of the “two dinucleotide binding domains” flavoproteins superfamily. A critical distinction between CoADR and all other PNDOR enzymes, including the Group 1 and Group 2 enzymes, lies in the fact that CoADR is the only disulfide reductase that uses a single active-site Cys in catalysis . The recent crystal structure for Staphylococcus aureus CoADR [SACoADR] revealed the resting state of the enzyme as containing a mixed disulfide of this Cys (SACoADR Cys43) with CoASH; this nonflavin redox center plays an essential role in catalysis. The structure also identified two Tyr residues in the active site, Tyr361′ and Tyr419′, that were proposed to be important in catalysis. <ref name="2exia">PMID:18399646 </ref><br />
<br />
<br />
=References=<br />
<references/><br />
Page originally authored by David Biel</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Human_lactoferrin&diff=1234939Human lactoferrin2011-04-26T22:04:39Z<p>Andrea Gorrell: New page: {{STRUCTURE_1dsn|PDB=1dsn|SCENE=}} =Amino-Terminal Half-Molecule of Human Lactoferrin= Human lactoferrin, LF, is a protein in the transferrin family. As such, it has the ability to tightly...</p>
<hr />
<div>{{STRUCTURE_1dsn|PDB=1dsn|SCENE=}}<br />
=Amino-Terminal Half-Molecule of Human Lactoferrin=<br />
Human lactoferrin, LF, is a protein in the transferrin family. As such, it has the ability to tightly bind iron in conjunction with a large-scale conformational change associated with iron binding and release.<ref name="faber">PMID:8594202</ref> These properties give lactoferrin the ability to regulate iron, and possibly other metal, ion levels in the fluids and secretions, such as milk, of animals.<ref name="faber" /> Lactoferrin is folded into two lobes: the N-terminal half, LF<sub>N</sub> ([[1dsn]]), and the C-terminal half, LF<sub>C</sub>. The two LF lobes have 37% homology and very similar tertiary structures; it has been suggested that the two lobes are the product of gene duplication.<ref name="farnaud" /> Each lobe of LF<sub>N</sub> is further subdivided into two similarly sized α and β domains (Figure 1); the <scene name='Sandbox_Reserved_302/Ligand_site/1'>iron binding site</scene> is situated in a deep cleft between the two domains.<ref name="faber" /><br />
<br />
In humans, lactoferrin is most abundant in milk, where it acts as part of the innate immune system.<ref name="sanchez">PMID:1599309</ref><br />
<br />
=Structure=<br />
[[Image:1DSN_Domains.png|left|thumb|'''Figure 1.''' Cartoon illustrating the alpha (green) and beta (magenta) domains of LF<sub>N</sub>]]<br />
The amino-terminal half-molecule of human lactoferrin (LF<sub>N</sub>) is comprised of a single 333 amino acid chain divided into two similarly-sized α and β domains. The iron binding site is located within a deep cleft between the lobes, where iron is bound by <scene name='Sandbox_Reserved_302/Helix_3_and_5/2'>Helices 3 and 5</scene> of the α and β domains, respectively. Iron, which is bound to a carboxylate ion, is bound by Asp60, Ala123, and Gly124. Although unwound in LF<sub>N</sub>, <scene name='Sandbox_Reserved_302/Pigtail/1'>residues 313 to 333</scene> form a helix when joined to LF<sub>C</sub>, forming the full LF protein.<ref name="faber" /><br />
<br />
The structure of LF<sub>N</sub> undergoes a dramatic conformational change upon iron binding. Upon iron binding, the two domains of LF<sub>N</sub> undergo a rigid 54.1º rotation about a <scene name='Sandbox_Reserved_302/Hinge/1'>screw axis</scene> that passes through Thr90 and Pro251.<ref name="gerstein">PMID:8230220</ref><br />
<br />
=Function & Application=<br />
Like transferrin, lactoferrin is an iron binding molecule, capable of regulating iron levels in bodily fluids and secretions.<ref name="faber" /> Unlike transferrin, only trace amounts of lactoferrin are found serum; however, lactoferrin can be found on concentrations ranging from 1 g/L to 7 g/L in milk.<ref name="sanchez" /> In human milk, lactoferrin is a part of the innate immune system, demonstrating anti-microbial properties.<ref name="sanchez" /><ref name="farnaud">PMID:14568385</ref> Many of lactoferrin's anti-microbial effects come from its ability to sequester iron, necessary for microbial growth.<ref name="farnaud" /> Lactoferrin also exhibits anti-viral activity by binding to the key viral features of several viruses including hepatitis c virus, rotavirus, poliovirus, and HIV.<ref name="strate">PMID:11675140</ref><br />
<br />
Because of the intrinsic antiviral properties of lactoferrin, it is of great interest as a drug delivery molecule. In this system, traditional antiviral medication, that can normally lead to a wide range of side-effects, can be targeted using lactoferrin, mitigating any ill effects.<ref name="strate" /><br />
<br />
=External Resources=<br />
[http://en.wikipedia.org/wiki/Lactoferrin Lactoferrin] at Wikipedia<br />
<br />
=References=<br />
<br />
<references /><br />
Page originally authored by Christian Axen</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Index.php/Sandbox_Reserved_337&diff=1225340Index.php/Sandbox Reserved 3372011-04-04T19:30:55Z<p>Andrea Gorrell: </p>
<hr />
<div>=Chorismate synthase=<br />
{{STRUCTURE_1ztb | PDB=1ztb | SCENE=Index.php/Sandbox_Reserved_337/Aroc/1 }}<br />
__TOC__<br />
Chorismate Synthase is the last enzyme present in the shikimate pathway<ref name= "planta"> PMID:9951731</ref>, a process which converts phosphoenolpyruvate, and erythrose 4-phosphate to chorismate in a series of seven steps.<ref name= "review"> PMID:15012217</ref> The shikimate pathway is essential in the production of the amino acids phenylalanine, tryptophan and tyrosine, all essential amino acids.<ref name= "main"> PMID:16459102</ref><br />
<br />
=Structure=<br />
This protein is in a unique form containing four subunits, and forming a homotetramer.<ref name= "pizza"> PMID:15095868</ref> The protein also contains a unique <scene name='Index.php/Sandbox_Reserved_337/Aroc2/1'>β-α-β sandwich fold</scene>.<ref name = "pizza"/><br />
<structure load= 1um0 size=250 frame =’1’ align=’left’ caption= 'Fig. 1. Chorismate synthase complexed with FMN, from PDB [[1um0]]'/><br />
The protein also has a cofactor bound within each monomer of the protein. This cofactor is FMN which is located within the <scene name='Index.php/Sandbox_Reserved_337/Fmn_cofactor1/1'>active site</scene> of the protein.<ref name = "pizza"/> Each of these cofactors are bound non-covalently within the protein in the reduced form.<ref name = "pizza"/><br />
<br />
==Function==<br />
The purpose of chorismate synthase is to convert 5-enolpyruvylshikimate 3-phosphate to chorismate, an essential step in the formation of indole rings used in the essential amino acids phenylalanine, tyrosine, and tryptophan.<ref name = "planta" /> The reduced flavin is believed to have one of a couple functions. It either has a structural role helping with formation of the structure, or reduces a sulfhydryl group in the protein residue, either aiding with binding or with having a catalytic effect.<ref name ="planta" /> The enzyme is monofunctional, requiring another enzyme to reduce the flavin cofactor, or addition of extra reduced flavin to add to the enzyme.<ref name = "review" /><br />
=Mechanism=<br />
In this reaction the 5-enolpyruvylshikimate 3-phosphate, is reduced forming a second double bond in the benzene ring attached to the phosphate.<ref name = "review" /> It appears that the phosphate group is reduced allowing the benzene ring to have a free electron pair to form a double bond with.<ref name = "review" /> As well the double bond which originally existed, experiences a hydrogen shift and the second double bond occurs to form resonance.<ref name = "review" /><br />
=References=<br />
<references /></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_325&diff=1225273Sandbox Reserved 3252011-04-04T17:09:17Z<p>Andrea Gorrell: </p>
<hr />
<div>{{STRUCTURE_2f6l | PDB=2f6l | Scene= }}<br />
{{Template:Sandbox_Reserved_BCMB307}}<br />
<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=Chorismate Mutase=<br />
==Introduction==<br />
The gene Rv1885c from ''Mycobacteria tuberculosis'' encodes for a non-functional chorismate mutase (*MtCM).<ref name="pizza" /> This non-functional mutase has a 33-amino-acid cleavable sequence.<ref name="pizza" /> Chorismate mutase is a vital enzyme in the shikimate pathway, which allows for the synthesis of tryptophan, tyrosine, and phenylalanine.<ref name="pizza" /> This protein acts at the first branch point of the shikimate pathway, making it a regulating step in the conversion of prephenate from chorismate.<ref name="CMW2"> PMID:11481470 </ref> Since chorismate mutase catalyzes a claisen rearrangement it can be considered an isomerase since it catalyzes rearrangements of isomers. Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reaction in comparision to the uncatalyzed reaction.<ref > P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350 </ref><br />
<br />
Chorismate mutase only occurs in bacteria, higher plants, and fungi, due to the fact that the shikimate pathway is only found in these organisms.<ref name="strat" /> In ''Escherichia coli'', chorismate mutase has a periplasmic destination.<ref name="pizza" /> In ''M. tuberculosis'' there is in abscence of a periplasmic compartment for chorismate mutase, so it secretes into the culture filtrate of ''M. tuberculosis''.<ref name="pizza" /> It is believed that a pseudoperiplasmic space might exist in ''M. tuberculosis''.<ref name="pizza" /><br />
<br />
The N-terminal sequence of ''M. tuberculosis'' chorismate mutase is able to function in ''E. coli'' which suggests that ''M. tuberulosis'' chorismate mutase belongs to the AroQ class of the chorismate mutases.<ref name="CMArt2"> PMID:15737998 </ref><br />
<br />
Rv1885c is synthesized along with the 33-amino-acid terminal sequence, which when expressed with ''E. coli'', is cleaved off the mature protein.<ref name="pizza" /> Chorismate mutase is the only example of an enzyme catalyzing a percyclic reaction.<ref name="strat"> PMID:10960481 </ref><br />
<br />
==Structure==<br />
<Structure load='2f6l' size='300' frame='true' align='left' caption='Chorismate Mutase' scene='Sandbox_Reserved_325/Chainbows/1' /><br />
<br />
Chorismate mutase is a homodimer which has a predominantly α-helical structure.<ref name="pizza" /> There are 10 α-helices spread across the two monomers of chorismate mutase.<ref name="pizza" /> Approximately 86% of the amino acid residues are in the α-helical formations.<ref name="pizza" /> The α-helical structure of *MtCM are similar to the chorismate mutases of ''S. cerevisae'' and ''E. coli''.<ref name="pizza" /> It holds its dimeric state in a protein concentration as low as 5 nM.<ref name="pizza" /> There are no β-sheets present in chorismate mutase.<ref name="CMArt2" /> <br />
<br />
Chorismate has an active site, which is used for the catalysis of the shikimate pathway.<ref name="pizza" /> The <scene name='Sandbox_Reserved_325/Active_site/1'>active site</scene> is made of Arg <sub>49</sub>,Lys <sub>60</sub>, Arg <sub>72</sub>, Thr <sub>105</sub>, Glu <sub>109</sub>, and Arg <sub>134</sub>.<ref name="pizza" /> This active site exists through electrostatic interactions with chorismate and hydrogen bonding between the amino acids <ref name="CMArt2" />. The active site forms within a single chain.<ref name="pizza" /> The active site can form without any help from the second half of the dimer.<ref name="pizza" /><br />
<br />
The molecular weight of *MtCM is 36,000 Da.<ref name="pizza" /> Based on that each monomeric subunit has a molecular weight of 18,474 Da, the molecular weight of the molecule supports the theory that it is a dimer.<ref name="pizza" /> This is also supported by that all chorismate mutases that occur naturally are either trimers or dimers.<ref name="pizza" /> ''M. tuberculosis'' chorismate mutase is similar to the chorismate mutases of yeast and ''E. coli'' in the regards that they all are homodimers.<ref name="CMArt2" /><br />
<br />
There are no allosteric regulatory sites on *MtCM, which supports the theory that chorismate mutase is not regulated by the aromatic amino acids that are the products of the shikimate pathway.<ref name="pizza" /><br />
<br />
There is one <scene name='Sandbox_Reserved_325/Disulfide/1'>disulfide bridge</scene> in chorismate mutase.<ref name="pizza" /> It is between Cys <sub>160</sub> and Cys <sub>193</sub>.<ref name="pizza" /><br />
<br />
*MtCM has a 33-amino-acid cleavable sequence.<ref name="pizza" /> The N-terminal sequence of ''M. tuberculosis'' chorismate mutase is able to function in ''E. coli'' which suggests that ''M. tuberulosis'' chorismate mutase belongs to the AroQ class of the chorismate mutases.<ref name="CMArt2" /> Another factor that suggests that ''M. tuberculosis'' chorismate mutase belongs to the AroQ class of chorismate mutases is that it has has a predominantly α-helical structure, which is similar to the chorismate mutases of ''E. coli'' and yeast, which also belong to the AroQ group of chorismate mutases.<ref name="CMArt2" /><br />
<br />
==Mechanism==<br />
in Michaelis-Menten kinetics chorismate mutase has Km of 0.5 ± 0.05 mM and Kcat of 60 s<sup>-1 </sup>.<ref name="pizza" /><br />
<br />
Chorismate mutase is an essential enzyme in the shikimate pathway.<ref name="pizza"> PMID:17146044 </ref> This pathway allows for the biosynthesis of aromatic amino acids tryptophan, tyrosine, and phenylalanine.<ref name="pizza" /> The production of tyrosine and phenylalanine is achieved by what is called a Claisen rearrangement.<ref name="pizza" /> First by converting chorismate to prephenate.<ref name="pizza" /> Prephenate then reacts with prephenate dehydratase and prephenate dehydrogenase which forms phenylpyruvate and hydroxyphenylpyruvate.<ref name="pizza" /> After this occurs, aminotransferase converts hydroxy-phenylpyruvate and phenylpyruvate to phenylalanine and tyrosine.<ref name="pizza" /> Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reaction, in comparison to the uncatalyzed reaction.<ref> P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350 </ref> It is the only example of an enzyme catalyzing a percyclic reaction. <ref name="strat"> PMID:10960481 </ref><br />
<br />
Chorismate mutase has optimal performance at 37 degrees Celcius and at pH 7.5, but it can still optimally a pH range from pH 4.0 to 7.5 <ref name="pizza" /><br />
<br />
<br />
==Chorismate Mutase and Tuberculosis==<br />
Tuberculosis has developed various mechanisms to survive in hostile environments.<ref name="CMArt2" /> The emergence of multi-drug resistant tuberculosis and other diseases such as AIDS compound the problem of how to treat tuberculosis.<ref name="CMArt2" /> Chorismate mutase may be involved in pathogenesis.<ref name="pizza" /> Researchers are currently looking into new antimicrobial drugs for diseases such as tuberculosis.<ref name="pizza" /> These new drugs would take advantage of the fact that chorismate mutase and the shikimate pathway do not occur in humans, to target and treat various forms of tuberculosis.<ref name="pizza" /> Chorismate mustase is believed to have a role in the survival of ''M. tuberculosis''.<ref name="CMArt2" /> Two genes in ''M. tuberculosis'', Rv0948c and Rv1885c code for chorismate mutase.<ref name="CMArt2" /> These help support ''M. tuberculosis'' when aromatic amino acids, such as tryptophan, tyrosine, and phenylalanine, are deficient.<ref name="CMArt2" /> Some researchers have proposed that a proline-rich section of ''M. tuberculosis'' chorismate mutase might be responsible for it binding to the surface receptors on the host cell marcophages<br />
.<ref name="CMW1"> PMID: 16752890 </ref><br />
<br />
==References==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_325&diff=1225271Sandbox Reserved 3252011-04-04T17:05:26Z<p>Andrea Gorrell: /* Mechanism */</p>
<hr />
<div>{{STRUCTURE_2f6l | PDB=2f6l | Scene= }}<br />
{{Template:Sandbox_Reserved_BCMB307}}<br />
<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=Chorismate Mutase=<br />
==Introduction==<br />
The gene Rv1885c from ''Mycobacteria tuberculosis'' encodes for a non-functional chorismate mutase (*MtCM).<ref name="pizza" /> This non-functional mutase has a 33-amino-acid cleavable sequence.<ref name="pizza" /> Chorismate mutase is a vital enzyme in the shikimate pathway, which allows for the synthesis of tryptophan, tyrosine, and phenylalanine.<ref name="pizza" /> This protein acts at the first branch point of the shikimate pathway, making it a regulating step in the conversion of prephenate from chorismate.<ref name="CMW2"> PMID:11481470 </ref> Since chorismate mutase catalyzes a claisen rearrangement it can be considered an isomerase since it catalyzes rearrangements of isomers. Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reaction in comparision to the uncatalyzed reaction.<ref > P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350</ref><br />
<br />
Chorismate mutase only occurs in bacteria, higher plants, and fungi, due to the fact that the shikimate pathway is only found in these organisms.<ref name="strat" /> In ''Escherichia coli'', chorismate mutase has a periplasmic destination.<ref name="pizza" /> In ''M. tuberculosis'' there is in abscence of a periplasmic compartment for chorismate mutase, so it secretes into the culture filtrate of ''M. tuberculosis''.<ref name="pizza" /> It is believed that a pseudoperiplasmic space might exist in ''M. tuberculosis''.<ref name="pizza" /><br />
<br />
The N-terminal sequence of ''M. tuberculosis'' chorismate mutase is able to function in ''E. coli'' which suggests that ''M. tuberulosis'' chorismate mutase belongs to the AroQ class of the chorismate mutases.<ref name="CMArt2"> PMID:15737998 </ref><br />
<br />
Rv1885c is synthesized along with the 33-amino-acid terminal sequence, which when expressed with ''E. coli'', is cleaved off the mature protein.<ref name="pizza" /> Chorismate mutase is the only example of an enzyme catalyzing a percyclic reaction.<ref name="strat"> PMID:10960481 </ref><br />
<br />
==Structure==<br />
<Structure load='2f6l' size='300' frame='true' align='left' caption='Chorismate Mutase' scene='Sandbox_Reserved_325/Chainbows/1' /><br />
<br />
Chorismate mutase is a homodimer which has a predominantly α-helical structure.<ref name="pizza" /> There are 10 α-helices spread across the two monomers of chorismate mutase.<ref name="pizza" /> Approximately 86% of the amino acid residues are in the α-helical formations.<ref name="pizza" /> The α-helical structure of *MtCM are similar to the chorismate mutases of ''S. cerevisae'' and ''E. coli''.<ref name="pizza" /> It holds its dimeric state in a protein concentration as low as 5 nM.<ref name="pizza" /> There are no β-sheets present in chorismate mutase.<ref name="CMArt2" /> <br />
<br />
Chorismate has an active site, which is used for the catalysis of the shikimate pathway.<ref name="pizza" /> The <scene name='Sandbox_Reserved_325/Active_site/1'>active site</scene> is made of Arg <sub>49</sub>,Lys <sub>60</sub>, Arg <sub>72</sub>, Thr <sub>105</sub>, Glu <sub>109</sub>, and Arg <sub>134</sub>.<ref name="pizza" /> This active site exists through electrostatic interactions with chorismate and hydrogen bonding between the amino acids <ref name="CMArt2" />. The active site forms within a single chain.<ref name="pizza" /> The active site can form without any help from the second half of the dimer.<ref name="pizza" /><br />
<br />
The molecular weight of *MtCM is 36,000 Da.<ref name="pizza" /> Based on that each monomeric subunit has a molecular weight of 18,474 Da, the molecular weight of the molecule supports the theory that it is a dimer.<ref name="pizza" /> This is also supported by that all chorismate mutases that occur naturally are either trimers or dimers.<ref name="pizza" /> ''M. tuberculosis'' chorismate mutase is similar to the chorismate mutases of yeast and ''E. coli'' in the regards that they all are homodimers.<ref name="CMArt2" /><br />
<br />
There are no allosteric regulatory sites on *MtCM, which supports the theory that chorismate mutase is not regulated by the aromatic amino acids that are the products of the shikimate pathway.<ref name="pizza" /><br />
<br />
There is one <scene name='Sandbox_Reserved_325/Disulfide/1'>disulfide bridge</scene> in chorismate mutase.<ref name="pizza" /> It is between Cys <sub>160</sub> and Cys <sub>193</sub>.<ref name="pizza" /><br />
<br />
*MtCM has a 33-amino-acid cleavable sequence.<ref name="pizza" /> The N-terminal sequence of ''M. tuberculosis'' chorismate mutase is able to function in ''E. coli'' which suggests that ''M. tuberulosis'' chorismate mutase belongs to the AroQ class of the chorismate mutases.<ref name="CMArt2" /> Another factor that suggests that ''M. tuberculosis'' chorismate mutase belongs to the AroQ class of chorismate mutases is that it has has a predominantly α-helical structure, which is similar to the chorismate mutases of ''E. coli'' and yeast, which also belong to the AroQ group of chorismate mutases.<ref name="CMArt2" /><br />
<br />
==Mechanism==<br />
in Michaelis-Menten kinetics chorismate mutase has Km of 0.5 ± 0.05 mM and Kcat of 60 s<sup>-1 </sup>.<ref name="pizza" /><br />
<br />
Chorismate mutase is an essential enzyme in the shikimate pathway.<ref name="pizza"> PMID:17146044 </ref> This pathway allows for the biosynthesis of aromatic amino acids tryptophan, tyrosine, and phenylalanine.<ref name="pizza" /> The production of tyrosine and phenylalanine is achieved by what is called a Claisen rearrangement.<ref name="pizza" /> First by converting chorismate to prephenate.<ref name="pizza" /> Prephenate then reacts with prephenate dehydratase and prephenate dehydrogenase which forms phenylpyruvate and hydroxyphenylpyruvate.<ref name="pizza" /> After this occurs, aminotransferase converts hydroxy-phenylpyruvate and phenylpyruvate to phenylalanine and tyrosine.<ref name="pizza" /> Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reaction, in comparison to the uncatalyzed reaction.<ref> P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350< /ref> It is the only example of an enzyme catalyzing a percyclic reaction.<ref name="strat"> PMID:10960481 </ref><br />
<br />
Chorismate mutase has optimal performance at 37 degrees Celcius and at pH 7.5, but it can still optimally a pH range from pH 4.0 to 7.5 <ref name="pizza" /><br />
<br />
<br />
==Chorismate Mutase and Tuberculosis==<br />
Tuberculosis has developed various mechanisms to survive in hostile environments.<ref name="CMArt2" /> The emergence of multi-drug resistant tuberculosis and other diseases such as AIDS compound the problem of how to treat tuberculosis.<ref name="CMArt2" /> Chorismate mutase may be involved in pathogenesis.<ref name="pizza" /> Researchers are currently looking into new antimicrobial drugs for diseases such as tuberculosis.<ref name="pizza" /> These new drugs would take advantage of the fact that chorismate mutase and the shikimate pathway do not occur in humans, to target and treat various forms of tuberculosis.<ref name="pizza" /> Chorismate mustase is believed to have a role in the survival of ''M. tuberculosis''.<ref name="CMArt2" /> Two genes in ''M. tuberculosis'', Rv0948c and Rv1885c code for chorismate mutase.<ref name="CMArt2" /> These help support ''M. tuberculosis'' when aromatic amino acids, such as tryptophan, tyrosine, and phenylalanine, are deficient.<ref name="CMArt2" /> Some researchers have proposed that a proline-rich section of ''M. tuberculosis'' chorismate mutase might be responsible for it binding to the surface receptors on the host cell marcophages<br />
.<ref name="CMW1"> PMID: 16752890 </ref><br />
<br />
==References==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_346&diff=1222709Sandbox Reserved 3462011-03-30T23:50:38Z<p>Andrea Gorrell: </p>
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{{Template:Sandbox_Reserved_BCMB307}}<br />
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{{STRUCTURE_1b4x|PDB=1b4x|SCENE=}}<br />
<br />
<br />
='''Aspartate Aminotransferase'''=<br />
==General Information==<br />
Aspartate Aminotransferase (AST), also know as Glutamic aspartic transaminase, glutamic oxaloacetic transaminase, and transaminase A., is an enzyme that is a member of the class-I pyridoxal-phosphate-dependent aminotransferase family.It is coded by the gene GOT1. It is a homodimer that is 413 amino acids long and serves a critical role in amino acid metabolism. Within prokaryote cells it is exclusively found in the cytosol, but in eukaryotic cells there are cytosol, mitochondrial, and chloroplast isozymes. <br />
<scene name='Sandbox_Reserved_346/Test/1'>Ligand</scene><br />
<br />
In the human body it is produced by the brain, skeletal muscles, liver, pancreas, red blood cells, and kidneys. The wide range of tissues in which it is made, separates it from the similar enzyme alanine transaminase (ALT) which is found primarily in the liver. The level of AST in the body can be used as a marker for tissue disease or damage. As well, AST and ALT levels can be compared to pinpoint whether tissue damage is primarily found within the liver.<br />
=='''Structure'''==<br />
<Structure load='1b4x' size='300' frame='true' align='left' caption='Ligand' scene='Sandbox_Reserved_346/Test/1'/><br />
<br />
=='''Function'''==<br />
=='''Clinical Applications'''==<br />
=='''Additional Resources'''==<br />
=='''References'''==</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_338&diff=1222642Sandbox Reserved 3382011-03-30T20:28:30Z<p>Andrea Gorrell: </p>
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<br />
{{STRUCTURE_2vnc | PDB=2vnc | SCENE=Sandbox_Reserved_338/2vnc/1}}<br />
<br />
==Introduction==<br />
A debranching enzyme is responsible for the breakdown of glycogen <ref name="Woo">PMID: 18703518 </ref>. There are two main groups of debranching enzymes, and they are separated according to their activity <ref name="Woo" />. The first group, consists of pullulanases and isoamylases which only exhibit α-1,6-glycosidase activity <ref name="Woo" />. Whereas the second group consists of glycogen debranching enzymes which possess two functions; both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />.<br />
<br />
TreX is an archaeal glycogen debranching enzyme from the species, ''Sulfolobus solfataricus'' <ref name="Woo" />. Even though TreX exhibits 74% sequence similarity to the isoamylase from ''Sulfolobus acidocaldarium'', TreX itself exhibits both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />. It functions to debranch the side chains of glycogen into maltodextrin, and subsequently TreY and TreZ convert the maltodextrin into trehalose <ref name="Woo" /> <ref name="Park"> doi:10.1080/10242420701806652 </ref>. TreX can be found in two oligomeric states, either as a dimer or as a tetramer. As TreX is an oligomer, each conformational state exhibits a different catalytic activity <ref name="Woo" />. <br />
<br />
<br />
there is a glutamate residue, <scene name='Sandbox_Reserved_338/2vnc/3'>residue 100</scene> that I am interested in showing.<br />
<br />
==Structure and Function==<br />
TreX is an oligomer, as it exists in a dimeric state and a tetrameric state, both of which are active in solution <ref name="Woo" />. All subunits are identical, where the monomer contains 612 amino acids in total <ref name="Woo" />. The polypeptide folds into two secondary structures, a β-sandwhich in the N terminal region, comprised of six β-strands and a (β/α)8 – barrel motif in the central domain, comprised of eight parallel α-strands which encircle eight parallel β-strands <ref name="Woo" />. The sequence composition of the TreX monomer exhibits a high degree of homology to the isoamylase debranching enzyme of Pseudomona, however the TreX monomer mainly deviates from this similarity in its substrate binding groove and the absence of a calcium ion ligand <ref name="Woo" />. <br />
<br />
In the dimeric form, the individual subunits are adjacent to each other, where both of the active sites face the same side <ref name="Woo" />. In the tetrameric form, two of the associated dimers face each other so as to position the active sites on the inside of the tetramer <ref name="Woo" />. <br />
<br />
More to come…<br />
<br />
<scene name='Sandbox_Reserved_338/Asp 363, Glu 399, and Asp 471/1'>TextToBeDisplayed</scene><br />
<scene name='Sandbox_Reserved_338/Residues/1'>TextToBeDisplayed</scene><br />
==Mechanism==<br />
<br />
This is my new image. [[Image:Glycogen_breakdown 2.png | thumb]]<br />
----<br />
<br />
==References==<br />
<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_324&diff=1220151Sandbox Reserved 3242011-03-28T18:44:49Z<p>Andrea Gorrell: </p>
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='''Human eIF2 (1q8k)'''=<br />
{{STRUCTURE_1q8k| PDB=1q8k | SCENE=Sandbox_Reserved_324/Default/1}}<br />
<br />
=Introduction=<br />
The translation of proteins requires three steps to occur; initiation, elongation and termination. With each step one or more factors is involved in aiding the process. In eukaryotes initiation has the most factors that are essential for initiation to occur. eIF2 is one of the many initiating factors needed for eukaryotic initiation to occur. It is needed for proper initiation to occur. It initially binds to eIF2β with in the presence of GTP. It then binds to Met-tRNA<sup>meti</sup> and releases the eIF2β. This specific eIF2(1q8k) is the human eIF2 <ref name="1q8k">PMID:15341733</ref>.<br />
<br />
=Structure=<br />
The human eIF2 structure was determined by NMR spectroscopy<ref name="1q8k"/>. The human eIF2 structure is a small structure made of two domains<ref name="1q8k"/>. These two domains have a unique characteristic in that they are mobile relative to the other domain<ref name="1q8k"/>. The N terminal domain (NTD) of the structure, of eIF2 structures, was discovered in previous years<ref name="dha"> doi:10.1016 </ref>, where the C-terminal domain (CTD) for the human eIF2 was undetermined until the whole structure was discovered. The CTD contains a αβ-fold, which remarkably has a similar appearance to the CTD of eEF1Bα, a translation elongation factor, even though there is no sequence homology between the two<ref name="1q8k"/>.<br />
<br />
=Function=<br />
<br />
<br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_324&diff=1220150Sandbox Reserved 3242011-03-28T18:43:48Z<p>Andrea Gorrell: </p>
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{{Template:Sandbox_Reserved_BCMB307}}<br />
<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
='''Human eIF2 (1q8k)'''=<br />
{{STRUCTURE_1q8k| PDB=1q8k | SCENE='Sandbox_Reserved_324/Default/1'}}<br />
<br />
=Introduction=<br />
The translation of proteins requires three steps to occur; initiation, elongation and termination. With each step one or more factors is involved in aiding the process. In eukaryotes initiation has the most factors that are essential for initiation to occur. eIF2 is one of the many initiating factors needed for eukaryotic initiation to occur. It is needed for proper initiation to occur. It initially binds to eIF2β with in the presence of GTP. It then binds to Met-tRNA<sup>meti</sup> and releases the eIF2β. This specific eIF2(1q8k) is the human eIF2 <ref name="1q8k">PMID:15341733</ref>.<br />
<br />
=Structure=<br />
The human eIF2 structure was determined by NMR spectroscopy<ref name="1q8k"/>. The human eIF2 structure is a small structure made of two domains<ref name="1q8k"/>. These two domains have a unique characteristic in that they are mobile relative to the other domain<ref name="1q8k"/>. The N terminal domain (NTD) of the structure, of eIF2 structures, was discovered in previous years<ref name="dha"> doi:10.1016 </ref>, where the C-terminal domain (CTD) for the human eIF2 was undetermined until the whole structure was discovered. The CTD contains a αβ-fold, which remarkably has a similar appearance to the CTD of eEF1Bα, a translation elongation factor, even though there is no sequence homology between the two<ref name="1q8k"/>.<br />
<br />
=Function=<br />
<br />
<br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_324&diff=1220149Sandbox Reserved 3242011-03-28T18:42:10Z<p>Andrea Gorrell: </p>
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{{Template:Sandbox_Reserved_BCMB307}}<br />
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='''Human eIF2 (1q8k)'''=<br />
{{STRUCTURE_1q8k| PDB=1q8k | SCENE= }}<br />
<br />
=Introduction=<br />
The translation of proteins requires three steps to occur; initiation, elongation and termination. With each step one or more factors is involved in aiding the process. In eukaryotes initiation has the most factors that are essential for initiation to occur. eIF2 is one of the many initiating factors needed for eukaryotic initiation to occur. It is needed for proper initiation to occur. It initially binds to eIF2β with in the presence of GTP. It then binds to Met-tRNA<sup>meti</sup> and releases the eIF2β. This specific eIF2(1q8k) is the human eIF2 <ref name="1q8k">PMID:15341733</ref>.<br />
<br />
=Structure=<br />
The human eIF2 structure was determined by NMR spectroscopy<ref name="1q8k"/>. The human eIF2 structure is a small structure made of two domains<ref name="1q8k"/>. These two domains have a unique characteristic in that they are mobile relative to the other domain<ref name="1q8k"/>. The N terminal domain (NTD) of the structure, of eIF2 structures, was discovered in previous years<ref name="dha"> doi:10.1016 </ref>, where the C-terminal domain (CTD) for the human eIF2 was undetermined until the whole structure was discovered. The CTD contains a αβ-fold, which remarkably has a similar appearance to the CTD of eEF1Bα, a translation elongation factor, even though there is no sequence homology between the two<ref name="1q8k"/>.<br />
<br />
=Function=<br />
<br />
<br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Index.php/Sandbox_Reserved_337&diff=1216693Index.php/Sandbox Reserved 3372011-03-22T20:56:56Z<p>Andrea Gorrell: </p>
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<div>=Chorismate synthase=<br />
{{STRUCTURE_1ztb | PDB=1ztb | SCENE=Index.php/Sandbox_Reserved_337/Aroc/1 }}<br />
__TOC__<br />
Chorismate Synthase is the last enzyme present in the shikimate pathway<ref name= "planta"> PMID:9951731</ref>, a process which converts phosphoenolpyruvate, and erythrose 4-phosphate to chorismate in a series of seven steps.<ref name= “review”> PMID:15012217</ref> The shikimate pathway is essential in the production of the amino acids phenylalanine, tryptophan and tyrosine, all essential amino acids.<ref name= "main"> PMID:16459102</ref><br />
<br />
=Structure=<br />
<structure load= 1um0 size=500 frame =’1’ align=’left’ caption= 'Fig. 1. Chorismate synthase complexed with FMN, from PDB 1um0' scene= /><ref name= "fuck"> PMID:15095868</ref><br />
<br />
==Function==<br />
<br />
=Mechanism=<br />
=References=<br />
<references /></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_333&diff=1216257Sandbox Reserved 3332011-03-17T21:57:54Z<p>Andrea Gorrell: </p>
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=Mevalonate Diphosphate Decarboxylase=<br />
<Structure load='2hk3' size='500' frame='true' align='right' caption='Fig 1 showing.....' scene='Insert optional scene name here' /><br />
==Introduction==<br />
:Mevalonate diphosphate decarboxylase (MDD) is an important enzyme required for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi <ref name = "Byres">PMID: 17583736 </ref>. MDD is a member of the GHMP (Galactokinase, Homoserine kinase, mevalonate kinase and phosphomevalonate kinase) enzyme family, and is responsible for the conversion of mevalonate diphosphate to isopentenyl pyrophosphate with the help of 1 ATP molecule<ref name = "Byres"/> <ref name = "Voynova"> PMID: 18823933 </ref>. Even though the kinases in the GHMP family differ in quaternary structure and ability to bind a wide variety of substrates, they share a characteristic alpha/beta fold and similar sequences <ref name = "Byres"/> <ref name = "ByresMartin"> PMID: 16511101 </ref>. Some GHMP kinases exist as dimers, some as tetramers and some as monomers <ref name = "Byres"/>. The amino acid residues in MDD are highly conserved across all species, indicating the specific important activity of the enzyme <ref name = "Byres"/>.<br />
<br />
<br />
==Structure==<br />
:Mevalonate diphosphate decarboxylase exists as a symmetrical dimer<ref name = "Byres"/> <ref name = "Voynova"/> <ref name ="ByresMartin"/> . The C-terminal domains of each monomer are symmetrically oriented towards one another around a solvent-filled channel <ref name = "Byres"/>. The dimer is stabilized between alpha helices 6 and 10 on the monomers, and also through salt bridge interactions, tyrosine and proline stacking, and hydrophobic interactions <ref name = "Byres"/>. The interface between the monomers is very small, with only 7% of the total surface area of the monomer engaged in the interface interaction <ref name = "Voynova"/>. This small interface between monomers is a characteristic of GHMP kinases <ref name = "Voynova"/>. Each monomer consists of a single polypeptide chain with 331 amino acid residues<ref name = "RCSB"> Kabsch W., Sander C. "Sequence/Structure details of Crystal Structure of mevalonate diphosphate decarboxylase from Staphylococcus aureus" RCSB Protein Databank, http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2HK3 </ref>. Each polypeptide chain has <scene name='Sandbox_Reserved_333/Mdd/3'>13 alpha helices and 15 beta sheets </scene> <ref name ="RCSB"/>. The active site on each monomer is a deep, highly charged cleft made up seven segments of polypeptide chain, which is located away from the other monomer, and is unaffected by dimerization <ref name = "Byres"/>. An ATP binding polypeptide segment called the P loop is also located near the active site <ref name = "Byres"/>. A total of 19 amino acid residue side chains are involved with substrate binding in the active site <ref name = "Byres"/>.<br />
<br />
==Reaction==<br />
:The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate, which is an important building block for all isoprenoids <ref name = "Andreassi"> PMID: 19485344 </ref>. Mevalonate diphosphate decarboxylase is the last enzyme in this pathway, and it converts mevalonate diphosphate to IPP (Fig 2) <ref name = "Andreassi"/>. The conversion of mevalonate diphosphate to isopentenyl pyrophosphate is a two-stage reaction <ref name = "Byres"/>. First, MDD binds an ATP molecule to the P loop near the active site, and the mevalonate diphosphate in the active site <ref name = "Byres"/>. Specifically, the Asp293 residue in the active site of MDD abstracts a proton from the C3 hydroxyl group of mevalonate diphosphate, creating a nucleophile that attacks the γ-phosphoryl group of ATP <ref name = "Byres"/>. The phosphorylation of the C3 carbon creates an unstable intermediate and a good leaving group on C3 (Fig 2)<ref name = "Byres"/>. The second stage of the reaction is when MDD dephosphorylates and decarboxylates the substrate, releasing isopentenyl pyrophosphate, inorganic phosphate, ADP and a CO2 molecule (Fig 2) <ref name = "Byres"/><ref name = "Voynova"/>. The IPP molecules can be joined together to make cholesterol or other isoprenoids.<br />
<br />
[[Image:Protopedia_figure.png|center|frame|Fig. 2 Phosphorylation of mevalonate diphosphate, followed by dephosphorylation and decarboxylation of the unstable intermeditae, yeilding isopentyl pyrophosphate, inorganic phosphate, carbon dioxide and ADP,catalyzed by mevalonate diphosphate decarboxylase]]<br />
<br />
==Significance==<br />
:Mevalonate diphosphate decarboxylase is a necessary enzyme in the cholesterol and isoprenoid biosynthesis pathway <ref name = "Byres"/> <ref name ="Krepkiy"> PMID: 15169949 </ref> <ref name = "Voynova"/> <ref name = "ByresMartin"/>. Without this enzyme, the cholesterol synthesis production decreases <ref name = "Krepkiy"/>, which can be detrimental to many organisms that rely on the formation of IPP for cholesterol, electron transport, membrane structures and anchors, and signaling pathways <ref name = "ByresMartin"/>. One such organism that requires MDD is the Trypanosoma bruceii, a parasite that causes [http://en.wikipedia.org/wiki/African_trypanosomiasis African Sleeping sickness] and is transmitted to the human bloodstream through the bite of the tsetse fly <ref name = "ByresMartin"/>. MDD was thought to be a potential target enzyme for an inhibitor that would disable the catalytic activity of MDD, thereby stopping IPP production and effectively killing the parasite <ref name = "ByresMartin"/>. It is believed now that the MDD found in Trypanosoma bruceii resembles human MDD too closely, and so it would be difficult to make a species specific inhibitor for MDD <ref name = "Byres"/>.<br />
<br />
{{STRUCTURE_2hk3|PDB=2hk3|SCENE=}}<br />
<br />
<br />
==References== <br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_333&diff=1216256Sandbox Reserved 3332011-03-17T21:47:38Z<p>Andrea Gorrell: </p>
<hr />
<div><!-- PLEASE DO NOT DELETE THIS TEMPLATE --><br />
{{Template:Sandbox_Reserved_BCMB307}}<br />
<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=Mevalonate Diphosphate Decarboxylase=<br />
<Structure load='2hk3' size='500' frame='true' align='right' caption='Fig 1 showing.....' scene='Insert optional scene name here' /><br />
==Introduction==<br />
:Mevalonate diphosphate decarboxylase (MDD) is an important enzyme required for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi <ref name = "Byres">PMID: 17583736 </ref>. MDD is a member of the GHMP (Galactokinase, Homoserine kinase, mevalonate kinase and phosphomevalonate kinase) enzyme family, and is responsible for the conversion of mevalonate diphosphate to isopentenyl pyrophosphate with the help of 1 ATP molecule<ref name = "Byres"/> <ref name = "Voynova"> PMID: 18823933 </ref>. Even though the kinases in the GHMP family differ in quaternary structure and ability to bind a wide variety of substrates, they share a characteristic alpha/beta fold and similar sequences <ref name = "Byres"/> <ref name = "ByresMartin"> PMID: 16511101 </ref>. Some GHMP kinases exist as dimers, some as tetramers and some as monomers <ref name = "Byres"/>. The amino acid residues in MDD are highly conserved across all species, indicating the specific important activity of the enzyme <ref name = "Byres"/>.<br />
<br />
<br />
==Structure==<br />
:Mevalonate diphosphate decarboxylase exists as a symmetrical dimer<ref name = "Byres"/> <ref name = "Voynova"/> <ref name ="ByresMartin"/> . The C-terminal domains of each monomer are symmetrically oriented towards one another around a solvent-filled channel <ref name = "Byres"/>. The dimer is stabilized between alpha helices 6 and 10 on the monomers, and also through salt bridge interactions, tyrosine and proline stacking, and hydrophobic interactions <ref name = "Byres"/>. The interface between the monomers is very small, with only 7% of the total surface area of the monomer engaged in the interface interaction <ref name = "Voynova"/>. This small interface between monomers is a characteristic of GHMP kinases <ref name = "Voynova"/>. Each monomer consists of a single polypeptide chain with 331 amino acid residues<ref name = "RCSB"> Kabsch W., Sander C. "Sequence/Structure details of Crystal Structure of mevalonate diphosphate decarboxylase from Staphylococcus aureus" RCSB Protein Databank, http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2HK3 </ref>. Each polypeptide chain has <scene name='Sandbox_Reserved_333/Mdd/3'>13 alpha helices and 15 beta sheets </scene> <ref name ="RCSB"/>. The active site on each monomer is a deep, highly charged cleft made up seven segments of polypeptide chain, which is located away from the other monomer, and is unaffected by dimerization <ref name = "Byres"/>. An ATP binding polypeptide segment called the P loop is also located near the active site <ref name = "Byres"/>. A total of 19 amino acid residue side chains are involved with substrate binding in the active site <ref name = "Byres"/>.<br />
<br />
==Reaction==<br />
:The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate, which is an important building block for all isoprenoids <ref name = "Andreassi"> PMID: 19485344 </ref>. Mevalonate diphosphate decarboxylase is the last enzyme in this pathway, and it converts mevalonate diphosphate to IPP (Fig 2) <ref name = "Andreassi"/>. The conversion of mevalonate diphosphate to isopentenyl pyrophosphate is a two-stage reaction <ref name = "Byres"/>. First, MDD binds an ATP molecule to the P loop near the active site, and the mevalonate diphosphate in the active site <ref name = "Byres"/>. Specifically, the Asp293 residue in the active site of MDD abstracts a proton from the C3 hydroxyl group of mevalonate diphosphate, creating a nucleophile that attacks the γ-phosphoryl group of ATP <ref name = "Byres"/>. The phosphorylation of the C3 carbon creates an unstable intermediate and a good leaving group on C3 (Fig 2)<ref name = "Byres"/>. The second stage of the reaction is when MDD dephosphorylates and decarboxylates the substrate, releasing isopentenyl pyrophosphate, inorganic phosphate, ADP and a CO2 molecule (Fig 2) <ref name = "Byres"/><ref name = "Voynova"/>. The IPP molecules can be joined together to make cholesterol or other isoprenoids.<br />
<br />
[[Image:Protopedia_figure.png]]<br />
:Fig. 2 Phosphorylation of mevalonate diphosphate, followed by dephosphorylation and decarboxylation of the unstable intermeditae, yeilding isopentyl pyrophosphate, inorganic phosphate, carbon dioxide and ADP,catalyzed by mevalonate diphosphate decarboxylase. <br />
==Significance==<br />
:Mevalonate diphosphate decarboxylase is a necessary enzyme in the cholesterol and isoprenoid biosynthesis pathway <ref name = "Byres"/><ref name = "Krepkiy"> PMID: 15169949 </ref> <ref name = "Voynova"/> <ref name = "ByresMartin"/>. Without this enzyme, the cholesterol synthesis production decreases <ref name = "Krepkiy"/>, which can be detrimental to many organisms that rely on the formation of IPP for cholesterol, electron transport, membrane structures and anchors, and signaling pathways <ref name = "ByresMartin"/>. One such organism that requires MDD is the Trypanosoma bruceii, a parasite that causes [http://en.wikipedia.org/wiki/African_trypanosomiasis African Sleeping sickness] and is transmitted to the human bloodstream through the bite of the tsetse fly <ref name = "ByresMartin"/>. MDD was thought to be a potential target enzyme for an inhibitor that would disable the catalytic activity of MDD, thereby stopping IPP production and effectively killing the parasite <ref name = "ByresMartin"/>. It is believed now that the MDD found in Trypanosoma bruceii resembles human MDD too closely, and so it would be difficult to make a species specific inhibitor for MDD <ref name = "Byres"/>.<br />
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{{STRUCTURE_2hk3|PDB=2hk3|SCENE=}}<br />
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<br />
==References== <references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_349&diff=1216079Sandbox Reserved 3492011-03-16T16:43:43Z<p>Andrea Gorrell: </p>
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<div>{{STRUCTURE_3eq1 | PDB=3eq1 | SCENE= }}<br />
Porphobilinogen deaminase (PBGD) also known as Hydroxymethylbilane synthase, is a monomeric polypeptide and is the third enzyme in the heme biosynthesis pathways in mammals<ref name="Raj">PMID: 19207107</ref>. It catalyses the polymerization of four porphobilinogen molecules to yield hydroxymethylbilane, a precursor in the formation of [[Porphyrin]]<ref name="Peter">PMID:3079571</ref>. Porphobilinogen deaminases are able to form surprisingly stable enzyme-substrate complexes with up to four pyrrole substrates interacting with the active site, a feature unique to the group of enzymes<ref name="Anderson">PMID:7354069</ref>. <scene name='Sandbox_Reserved_349/Dpm/2'>Dipyrromethane (DPM)</scene>, a cofactor unique to porphobilinogen deaminases, is thought to stabilize these interactions at each of the two active domains<ref name="Peter">PMID:3079571</ref>. Mutations in the human PBGD (hPBGD) gene are responsible for the condition Acute Intermittent Porphyria (AIP) in humans<ref name="Raj">PMID: 19207107</ref>.<br />
=Porphobilinogen deaminase=<br />
__TOC__<br />
==Structure==<br />
<Structure load='3eq1' size='250' frame='true' align='left' scene='Sandbox_Reserved_349/Dpm/2' /><br />
PBGD is a monomeric three-domain polypeptide with each domain consisting of approximately 110 amino acids. The human variant has an additional 29 residue loop in domain three that extends hydrogen bonding across domains one and three while ''E.coli'' PBGD is lacking this extended loop <ref name="Raj">PMID: 19207107</ref>. In the active site, a unique molecule known as <scene name='Template:Sandbox_Reserved_349/Dpm/3'>Dipyrromethane</scene> interacts with porphobilinogen and anchors it in place<ref name="Raj">PMID: 19207107</ref>. Ordered <scene name='Sandbox_Reserved_349/So4_hbond/1'>sulfate ions</scene> are also hydrogen bonded with Arg26 and Ser28 residues near the active site that are highly conserved amongst human and ''E.coli'' variants of PBGD<ref name="Raj">PMID: 19207107</ref>.<br />
Although PBGD appears to have hydrogen bonding capabilities between two identical PBGD units, at physiological pH, these interactions account for a dimer interface of approximately 5% while average dimer interface between subunits is 16%<ref name="Raj">PMID: 19207107</ref>. Therefore, it is generally assumed that this protein is active naturally as a monomeric enzyme, while the crystalline form is a homo-dimeric structure of two identical PBGD subunits<ref name="Raj">PMID: 19207107</ref>.<br />
==Function==<br />
===Mechanism===<br />
<br />
===Acute Intermittent Porphyria===<br />
==Importance of hPBGD==<br />
==References==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_349&diff=1216078Sandbox Reserved 3492011-03-16T16:40:31Z<p>Andrea Gorrell: </p>
<hr />
<div>{{STRUCTURE_3eq1 | PDB=3eq1 | SCENE= }}<br />
Porphobilinogen deaminase (PBGD) also known as Hydroxymethylbilane synthase, is a monomeric polypeptide and is the third enzyme in the heme biosynthesis pathways in mammals<ref name="Raj">PMID: 19207107</ref>. It catalyses the polymerization of four porphobilinogen molecules to yield hydroxymethylbilane, a precursor in the formation of [[Porphyrin]]<ref name="Peter">PMID:3079571</ref>. Porphobilinogen deaminases are able to form surprisingly stable enzyme-substrate complexes with up to four pyrrole substrates interacting with the active site, a feature unique to the group of enzymes<ref name="Anderson">PMID:7354069</ref>. <scene name='Sandbox_Reserved_349/Dpm/2'>Dipyrromethane (DPM)</scene>, a cofactor unique to porphobilinogen deaminases, is thought to stabilize these interactions at each of the two active domains<ref name="Peter">PMID:3079571</ref>. Mutations in the human PBGD (hPBGD) gene are responsible for the condition Acute Intermittent Porphyria (AIP) in humans<ref name="Raj">PMID: 19207107</ref>.<br />
=Porphobilinogen deaminase=<br />
__TOC__<br />
==Structure==<br />
<Structure load='3eq1' size='250' frame='true' align='left' scene='Sandbox_Reserved_349/Dpm/2' /><br />
PBGD is a monomeric three-domain polypeptide with each domain consisting of approximately 110 amino acids. The human variant has an additional 29 residue loop in domain three that extends hydrogen bonding across domains one and three while ''E.coli'' PBGD is lacking this extended loop <ref name="Raj">PMID: 19207107</ref>. In the active site, a unique molecule known as <scene name='Template:Sandbox_Reserved_349/Dpm_site/3'>Dipyrromethane</scene> interacts with porphobilinogen and anchors it in place<ref name="Raj">PMID: 19207107</ref>. Ordered <scene name='Sandbox_Reserved_349/So4_hbond/1'>sulfate ions</scene> are also hydrogen bonded with Arg26 and Ser28 residues near the active site that are highly conserved amongst human and ''E.coli'' variants of PBGD<ref name="Raj">PMID: 19207107</ref>.<br />
Although PBGD appears to have hydrogen bonding capabilities between two identical PBGD units, at physiological pH, these interactions account for a dimer interface of approximately 5% while average dimer interface between subunits is 16%<ref name="Raj">PMID: 19207107</ref>. Therefore, it is generally assumed that this protein is active naturally as a monomeric enzyme, while the crystalline form is a homo-dimeric structure of two identical PBGD subunits<ref name="Raj">PMID: 19207107</ref>.<br />
==Function==<br />
===Mechanism===<br />
<br />
===Acute Intermittent Porphyria===<br />
==Importance of hPBGD==<br />
==References==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_321&diff=1213569Sandbox Reserved 3212011-03-15T20:22:04Z<p>Andrea Gorrell: </p>
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'''InhA'''<br />
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by Kelly Hrywkiw<br />
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{{STRUCTURE_2h9i | PDB=2h9i | SCENE= }}</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_338&diff=1213565Sandbox Reserved 3382011-03-15T19:21:48Z<p>Andrea Gorrell: </p>
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{{STRUCTURE_2vnc | PDB=2vnc | SCENE=Sandbox_Reserved_338/2vnc/1}}<br />
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A debranching enzyme is responsible for the breakdown of glycogen <ref name="Woo"> PMID:18703518 </ref>. There are two main groups of debranching enzymes, and they are separated according to their activity <ref name="Woo" />. The first group, consisting of [http://en.wikipedia.org/wiki/Pullulanase pullulanase] and isoamylases which only possess one function α-1,6-glycosidase activity <ref name="Woo" />. Whereas the second group consists of glycogen debranching enzymes which possess two functions, both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />. <br />
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there is a glutamate residue, <scene name='Sandbox_Reserved_338/2vnc/3'>residue 100</scene> that I am interested in showing.<br />
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==References==<br />
<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_338&diff=1213563Sandbox Reserved 3382011-03-15T19:19:00Z<p>Andrea Gorrell: </p>
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{{Template:Sandbox_Reserved_BCMB307}}<br />
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{{STRUCTURE_2vnc | PDB=2vnc | SCENE=Sandbox_Reserved_338/2vnc/1}}<br />
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A debranching enzyme is responsible for the breakdown of glycogen <ref name="Woo"> PMID:18703518 </ref>. There are two main groups of debranching enzymes, and they are separated according to their activity <ref name="Woo" />. The first group, consisting of [http://en.wikipedia.org/wiki/Pullulanase pullulanase] and isoamylases which only possess one function α-1,6-glycosidase activity <ref name="Woo" />. Whereas the second group consists of glycogen debranching enzymes which possess two functions, both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />. <br />
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<scene name='Sandbox_Reserved_338/2vnc/3'>Test scene</scene><br />
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==References==<br />
<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_338&diff=1213561Sandbox Reserved 3382011-03-15T19:12:40Z<p>Andrea Gorrell: </p>
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{{Template:Sandbox_Reserved_BCMB307}}<br />
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{{STRUCTURE_2vnc | PDB=2vnc | SCENE=Sandbox_Reserved_338/2vnc/1}}<br />
<br />
A debranching enzyme is responsible for the breakdown of glycogen <ref name="Woo"> PMID:18703518 </ref>. There are two main groups of debranching enzymes, and they are separated according to their activity <ref name="Woo" />. The first group, consisting of [http://en.wikipedia.org/wiki/Pullulanase pullulanase] and isoamylases which only possess one function α-1,6-glycosidase activity <ref name="Woo" />. Whereas the second group consists of glycogen debranching enzymes which possess two functions, both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />. <br />
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==References==<br />
<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_338&diff=1213560Sandbox Reserved 3382011-03-15T19:11:55Z<p>Andrea Gorrell: </p>
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{{Template:Sandbox_Reserved_BCMB307}}<br />
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{{STRUCTURE_2vnc | PDB=2vnc | SCENE=Sandbox_Reserved_338/2vnc/1}}<br />
<br />
A debranching enzyme is responsible for the breakdown of glycogen <ref name="Woo"> PMID:18703518 </ref>. There are two main groups of debranching enzymes, and they are separated according to their activity <ref name="Woo" />. The first group, consisting of [http://wikipedia.org/pullulanase pullulanase] and isoamylases which only possess one function α-1,6-glycosidase activity <ref name="Woo" />. Whereas the second group consists of glycogen debranching enzymes which possess two functions, both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />. <br />
<br />
<br />
<br />
<br />
==References==<br />
<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_338&diff=1213559Sandbox Reserved 3382011-03-15T19:10:43Z<p>Andrea Gorrell: </p>
<hr />
<div><!-- PLEASE DO NOT DELETE THIS TEMPLATE --><br />
{{Template:Sandbox_Reserved_BCMB307}}<br />
<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
<br />
{{STRUCTURE_2vnc | PDB=2vnc | SCENE=Sandbox_Reserved_338/2vnc/1}}<br />
<br />
A debranching enzyme is responsible for the breakdown of glycogen <ref name="Woo"> PMID:18703518 </ref>. There are two main groups of debranching enzymes, and they are separated according to their activity <ref name="Woo" />. The first group, consisting of [[pullulanase]] and isoamylases which only possess one function α-1,6-glycosidase activity <ref name="Woo" />. Whereas the second group consists of glycogen debranching enzymes which possess two functions, both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />. <br />
<br />
<br />
<br />
<br />
==References==<br />
<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_338&diff=1213558Sandbox Reserved 3382011-03-15T19:10:11Z<p>Andrea Gorrell: </p>
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<div><!-- PLEASE DO NOT DELETE THIS TEMPLATE --><br />
{{Template:Sandbox_Reserved_BCMB307}}<br />
<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
<br />
{{STRUCTURE_2vnc | PDB=2vnc | SCENE=Sandbox_Reserved_338/2vnc/1}}<br />
<br />
A debranching enzyme is responsible for the breakdown of glycogen <ref name="Woo"> PMID:18703518 </ref>. There are two main groups of debranching enzymes, and they are separated according to their activity <ref name="Woo" />. The first group, consisting of [[pullulanases]] and isoamylases which only possess one function α-1,6-glycosidase activity <ref name="Woo" />. Whereas the second group consists of glycogen debranching enzymes which possess two functions, both α-1,6-glycosidase and α-1,4-transferase activity <ref name="Woo" />. <br />
<br />
<br />
<br />
<br />
==References==<br />
<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_333&diff=1203591Sandbox Reserved 3332011-03-11T17:55:48Z<p>Andrea Gorrell: </p>
<hr />
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{{Template:Sandbox_Reserved_BCMB307}}<br />
<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=Mevalonate Diphosphate Decarboxylase=<br />
{{STRUCTURE_2hk3|PDB=2hk3|SCENE=Sandbox_Reserved_333/Fig2/1}}<br />
<br />
==Introduction==<br />
:Mevalonate diphosphate decarboxylase (MDD) is an important enzyme required for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi <ref name = "Byres"> 17583736 </ref>. MDD is a member of the GHMP (Galactokinase, Homoserine kinase, mevalonate kinase and phosphomevalonate kinase) enzyme family, and is responsible for the conversion of mevalonate diphosphate to isopentenyl pyrophosphate with the help of 1 ATP molecule<ref name = "Byres"/> <ref name = "Voynova"> 18823933 </ref>. Even though the kinases in the GHMP family differ in quaternary structure and ability to bind a wide variety of substrates, they share a characteristic alpha/beta fold and similar sequences <ref name = "Byres"/> <ref name = "ByresMartin"> 16511101 </ref>. Some GHMP kinases exist as dimers, some as tetramers and some as monomers <ref name = "Byres"/>. The amino acid residues in MDD are highly conserved across all species, indicating the specific important activity of the enzyme <ref name = "Byres"/>.<br />
<scene name='Sandbox_Reserved_333/Fig2/1'>gggggg</scene><br />
<br />
==Structure==<br />
:Mevalonate diphosphate decarboxylase exists as a symmetrical dimer<ref name = "Byres"/> <ref name = "Voynova"/> <ref name ="ByresMartin"/> . The C-terminal domains of each monomer are symmetrically oriented towards one another around a solvent-filled channel <ref name = "Byres"/>. The dimer is stabilized between alpha helices 6 and 10 on the monomers, and also through salt bridge interactions, tyrosine and proline stacking, and hydrophobic interactions <ref name = "Byres"/>. The interface between the monomers is very small, with only 7% of the total surface area of the monomer engaged in the interface interaction <ref name = "Voynova"/>. This small interface between monomers is a characteristic of GHMP kinases <ref name = "Voynova"/>. Each monomer consists of a single polypeptide chain with 331 amino acid residues. Each polypeptide chain has 13 alpha helices and 15 beta chains. The active site on each monomer is a deep, highly charged cleft made up seven segments of polypeptide chain, which is located away from the other monomer, and is unaffected by dimerization <ref name = "Byres"/>. An ATP binding polypeptide segment called the P loop is also located near the active site <ref name = "Byres"/>. A total of 19 amino acid residue side chains are involved with substrate binding in the active site <ref name = "Byres"/>.<br />
<br />
==Reaction==<br />
:The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate, which is an important building block for all isoprenoids <ref name = "Andreassi"> 19485344 </ref>. Mevalonate diphosphate decarboxylase is the last enzyme in this pathway, and it converts mevalonate diphosphate to IPP <ref name = "Andreassi"/>. The conversion of mevalonate diphosphate to isopentenyl pyrophosphate is a two-stage reaction <ref name = "Byres"/>. First, MDD binds an ATP molecule to the P loop near the active site, and the mevalonate diphosphate in the active site <ref name = "Byres"/>. Specifically, the Asp293 residue in the active site of MDD abstracts a proton from the C3 hydroxyl group of mevalonate diphosphate, creating a nucleophile that attacks the γ-phosphoryl group of ATP <ref name = "Byres"/>. The phosphorylation of the C3 carbon creates an unstable intermediate and a good leaving group on C3 <ref name = "Byres"/>. The second stage of the reaction is when MDD dephosphorylates and decarboxylates the substrate, releasing isopentenyl pyrophosphate, inorganic phosphate, ADP and a CO2 molecule <ref name = "Byres"/><ref name = "Voynova"/>. The IPP molecules can be joined together to make cholesterol or other isoprenoids.<br />
<br />
==Significance==<br />
Mevalonate diphosphate decarboxylase is a necessary enzyme in the cholesterol and isoprenoid biosynthesis pathway <ref name = "Byres"/><ref name = "Krepkiy"> 15169949 </ref> <ref name = "Voynova"/> <ref name = "ByresMartin"/>. Without this enzyme, the cholesterol synthesis production decreases <ref name = "Krepkiy"/>, which can be detrimental to many organisms that rely on the formation of IPP for cholesterol, electron transport, membrane structures and anchors, and signaling pathways <ref name = "ByresMartin"/>. One such organism that requires MDD, is the Trypanosoma bruceii, a parasite that is transmitted to the human bloodstream through the bite of the tsetse fly, that causes African Sleeping sickness <ref name = "ByresMartin"/>. MDD was thought to be a potential target enzyme for an inhibitor that would disable the catalytic activity of MDD, thereby stopping IPP production and effectively killing the parasite <ref name = "ByresMartin"/>. It is believed now that the MDD found in Trypanosoma bruceii resembles human MDD too closely, and so it would be difficult to make a species specific inhibitor for MDD <ref name = "Byres"/>.<br />
<br />
==References==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_333&diff=1203590Sandbox Reserved 3332011-03-11T17:50:08Z<p>Andrea Gorrell: </p>
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=Mevalonate Diphosphate Decarboxylase=<br />
{{STRUCTURE_2hk3|PDB=2hk3|SCENE=Sandbox_Reserved_333/Fig2/1}}<br />
<br />
==Introduction==<br />
:Mevalonate diphosphate decarboxylase (MDD) is an important enzyme required for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi <ref name = "Byres"> 17583736 </ref>. MDD is a member of the GHMP (Galactokinase, Homoserine kinase, mevalonate kinase and phosphomevalonate kinase) enzyme family, and is responsible for the conversion of mevalonate diphosphate to isopentenyl pyrophosphate with the help of 1 ATP molecule<ref name = "Byres"/> <ref name = "Voynova"> 18823933 </ref>. Even though the kinases in the GHMP family differ in quaternary structure and ability to bind a wide variety of substrates, they share a characteristic alpha/beta fold and similar sequences <ref name = "Byres"/> <ref name = "ByresMartin"> 16511101 </ref>. Some GHMP kinases exist as dimers, some as tetramers and some as monomers <ref name = "Byres"/>. The amino acid residues in MDD are highly conserved across all species, indicating the specific important activity of the enzyme <ref name = "Byres"/>.<br />
<scene name='Sandbox_Reserved_333/Fig2/1'>gggggg</scene><br />
<br />
==Structure==<br />
:Mevalonate diphosphate decarboxylase exists as a symmetrical dimer<ref name = "Byres"/> <ref name = "Voynova"/> <ref name ="ByresMartin"/> . The C-terminal domains of each monomer are symmetrically oriented towards one another around a solvent-filled channel <ref name = "Byres"/>. The dimer is stabilized between alpha helices 6 and 10 on the monomers, and also through salt bridge interactions, tyrosine and proline stacking, and hydrophobic interactions <ref name = "Byres"/>. The interface between the monomers is very small, with only 7% of the total surface area of the monomer engaged in the interface interaction <ref name = "Voynova"/>. This small interface between monomers is a characteristic of GHMP kinases <ref name = "Voynova"/>. Each monomer consists of a single polypeptide chain with 331 amino acid residues. Each polypeptide chain has 13 alpha helices and 15 beta chains. The active site on each monomer is a deep, highly charged cleft made up seven segments of polypeptide chain, which is located away from the other monomer, and is unaffected by dimerization <ref name = "Byres"/>. An ATP binding polypeptide segment called the P loop is also located near the active site <ref name = "Byres"/>. A total of 19 amino acid residue side chains are involved with substrate binding in the active site <ref name = "Byres"/>.<br />
<br />
==Reaction==<br />
:The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate, which is an important building block for all isoprenoids <ref name = "Andreassi"> 19485344 </ref>. Mevalonate diphosphate decarboxylase is the last enzyme in this pathway, and it converts mevalonate diphosphate to IPP <ref name = "Andreassi"/>. The conversion of mevalonate diphosphate to isopentenyl pyrophosphate is a two-stage reaction <ref name = "Byres"/>. First, MDD binds an ATP molecule to the P loop near the active site, and the mevalonate diphosphate in the active site <ref name = "Byres"/>. Specifically, the Asp293 residue in the active site of MDD abstracts a proton from the C3 hydroxyl group of mevalonate diphosphate, creating a nucleophile that attacks the γ-phosphoryl group of ATP <ref name = "Byres"/>. The phosphorylation of the C3 carbon creates an unstable intermediate and a good leaving group on C3 <ref name = "Byres"/>. The second stage of the reaction is when MDD dephosphorylates and decarboxylates the substrate, releasing isopentenyl pyrophosphate, inorganic phosphate, ADP and a CO2 molecule <ref name = "Byres"/><ref name = "Voynova"/>. The IPP molecules can be joined together to make cholesterol or other isoprenoids.<br />
<br />
==Significance==<br />
Mevalonate diphosphate decarboxylase is a necessary enzyme in the cholesterol and isoprenoid biosynthesis pathway <ref name = "Byres"/><ref name = "Krepkiy"> 15169949 <ref/> <ref name = "Voynova"/> <ref name = "ByresMartin"/>. Without this enzyme, the cholesterol synthesis production decreases <ref name = "Krepkiy"/>, which can be detrimental to many organisms that rely on the formation of IPP for cholesterol, electron transport, membrane structures and anchors, and signaling pathways <ref name = "ByresMartin"/>. One such organism that requires MDD, is the Trypanosoma bruceii, a parasite that is transmitted to the human bloodstream through the bite of the tsetse fly, that causes African Sleeping sickness <ref name = "ByresMartin"/>. MDD was thought to be a potential target enzyme for an inhibitor that would disable the catalytic activity of MDD, thereby stopping IPP production and effectively killing the parasite <ref name = "ByresMartin"/>. It is believed now that the MDD found in Trypanosoma bruceii resembles human MDD too closely, and so it would be difficult to make a species specific inhibitor for MDD <ref name = "Byres"/>.<br />
<br />
==References==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_309&diff=1200905Sandbox Reserved 3092011-03-04T04:28:13Z<p>Andrea Gorrell: </p>
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=Introduction=<br />
__TOC__<br />
=section 1=<br />
{{STRUCTURE_2cdn|PDB=2cdn|SCENE=}}<br />
==section 1.1==<br />
==section 1.2==<br />
===subsection 1.21===<br />
=section2=<br />
<scene name='Sandbox_Reserved_309/Ligand/1'>Ligand</scene><br />
*bullet<br />
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<Structure load=2cdn size='200' frame='true' align='left' caption= 'this is a ligand' scene='Sandbox_Reserved_309/Ligand/1'/><br />
α<br />
<ref name=lastname1stauthor>PMID:number </ref><br />
=references=<br />
<references/><br />
hi my name is <br/> Hezzy</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_348&diff=1200860Sandbox Reserved 3482011-03-03T23:56:11Z<p>Andrea Gorrell: </p>
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__TOC__<br />
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=Section 1=<br />
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[[Image:1ppb.png|300px|This are a caption.]]<br />
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<ref name="Placeholder">PMID:2583108</ref><br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_348&diff=1200858Sandbox Reserved 3482011-03-03T23:55:08Z<p>Andrea Gorrell: </p>
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__TOC__<br />
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{|<br />
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<ref name="Placeholder">PMID:2583108</ref><br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_348&diff=1200849Sandbox Reserved 3482011-03-03T23:49:55Z<p>Andrea Gorrell: </p>
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<ref name="Placeholder">PMID:2583108</ref><br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_348&diff=1200791Sandbox Reserved 3482011-03-03T23:08:28Z<p>Andrea Gorrell: </p>
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{{ STRUCTURE_1ppb | PDB=1ppb | SCENE= }}</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Adenylosuccinate_Synthetase&diff=1200411Adenylosuccinate Synthetase2011-03-02T08:21:08Z<p>Andrea Gorrell: </p>
<hr />
<div>{{STRUCTURE_3hid | PDB=3hid | SCENE= }}<br />
<br />
==Introduction==<br />
Adenylosuccinate Synthetase (AdSS) is part of the [http://en.wikipedia.org/wiki/Ligase Ligase] family of enzymes<ref>http://www.pdb.org/pdb/explore/explore.do?structureId=3HID</ref>. Ligase enzymes commonly 'glue' two different molecules together and create a new chemical bond. <br />
<br />
Its systematic name is IMP:L-aspartate ligase. It is mainly involved in purine bio-synthesis. It does this by catalyzing the GTP dependent changeover of IMP and aspartic acid to AMP in the presense of Mg<sup>2+</sup>.<ref>PMID:1698173 </ref> In Humans, AdSS catalyzes the first committed step in the purine nucleotide cycle by the de novo synthesis of adenosine monophosphate.<ref>PMID:649264</ref><br />
<br />
AdSS (3hid) was isolated from [http://en.wikipedia.org/wiki/Yersinia_pestis <i>Yersinia pestis CO92</i>]and can be found in a variety of organisms ranging from yeast to bacteria to humans. Its crystal structure was determined using x-ray diffraction at a resolution of 1.60 Angstoms. The gene is located on chromosome 1 q44, in humans and is expressed in the majority of an organisms cells.<br />
<br />
==Structure== <br />
<br />
The AdSS enzyme is a dimer consisting of two identical monomeric subunits. The main structural component of each monomer is a centrally located beta sheet that is comprised of 10 strands. Nine of the 10 strands are parallel while the 10th strand is anti-parallel with respect to the other 9 strands. There are also several other secondary structures including 2 small 3/10 helices and two anti-parallel sheets consisting of 2 and 3 strands respectively. Additionally there are 11 alpha helices.<ref name=crystal>PMID:8244965</ref> AdSS has three major binding sites, one for GTP, one for IMP and its active site. The active site, in yellow, and ligand molecules in orange can be seen <scene name='Sandbox_187/Active_site_and_ligand/1'>here</scene>.<br />
<br />
The major fold of this protein is unique and has not been documented in any other type of protein. The active site itself consists of a crevice consisting of Gly12, Gly15, Gly17, Lys18, Ile19, and Lys331. The other side of the crevice contains Lysine 140 and Arg147, which are located in the region between the two monomers. Asp231 is bonded to Lys140 in a salt bridge and its carbonyl atom is hydrogen bonded to Arg147. Also, none of cysteine residues are bound to each other in disulphide bonds.<ref name=crystal /> <br />
<br />
Helices are highlighted in green <scene name='Sandbox_187/Green_helices/1'>here</scene> and beta sheets are shown in orange <scene name='Sandbox_187/Beta_sheets/1'>here</scene>.<br />
<br />
AdSS has an optimal pH of 6.5 and a denatures at pH 7.4.<ref>PMID:1548</ref> It has a melting point of 85 degrees Celsius.<ref>PMID:691098</ref><br />
<br />
==Reaction Mechanism==<br />
AdSS undergoes the following amination reaction:<br />
<br />
GTP + IMP + L-Asp -> GDP + phosphate + N6-(1,2-dicarboxyethyl)-AMP<ref>PMID:4436310</ref><br />
<br />
[[Image:gtp.gif|GTP]] + [[Image:imp.gif|IMP]] +[[Image:L-Aspartate.gif|L-Aspartate]] -> [[Image:GDP.gif|GDP]] + [[Image:phosphate.gif|Phosphate]] + [[Image:adenylosuccinate.gif|Adenylosuccinate]]<br />
<br />
The 6-O of inosine is displaced by aspartate which yields adenylosuccinate. The presence, or over abundance of AMP, GMP, GDP and adenylosuccinate acts as a feedback inhibitor for AdSS.<ref>PMID:662843</ref><br />
<br />
Binding of GTP alone is not sufficient to induce a conformational change in the enzyme. IMP, coupled with an acetate ion invoke a conformational change which helps prepare the active site for catalysis. The reaction proceeds as follows: The gamma phosphoryl group of GTP is transferred to the 6-keto group of IMP which causes the displacement of an inorganic phosphorus molecule, Pi, from L-Aspartate. This leads to the formation of an adenylosuccinate molecule.<ref>PMID: 11560929</ref><br />
<br />
==Medical Implications==<br />
<br />
Defects in the gene product can result in a wide variety of diseases such as Acidosis, Gout, Neoplasms, Sarcoma, Leukemia and Lymphoma<ref>PMID:7438071</ref>. Since AdSS plays a crucial role in purine catalysis, it is a choice target for anti tumor drugs and antibiotics. A variety of enzymes are found to be improperly balanced in cancer cells, including AdSS which is found to be over expressed 5.5 times as much as it would normally be.<ref>PMID: 6861338</ref><br />
<br />
==References== <br />
<br />
<references /></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Glutamine_synthetase&diff=1064583Glutamine synthetase2010-03-31T22:52:36Z<p>Andrea Gorrell: </p>
<hr />
<div>=''' Glutamine Synthetase '''=<br />
<br />
<br />
<br />
==Structure==<br />
{{STRUCTURE_2gls| PDB=2gls | SCENE=Sandbox_169/2gls/1 }}<br />
An unrefined structure of glutamine synthetase is made of two layers, each containing 6 subunits, for a total of 12 subunits. <ref name="Yamashita">PMID:2572586 </ref> Each subunit contains an <scene name='Sandbox_169/Mn_in_the_active_site/2'>active site </scene>which is defined by a cylindrical shape formed by six antiparalel β starnds contributed by one subunit and two more strands by the neighbouring subunit. <ref name="Yamashita"/> In each cylindrical active site there are two Mn2+ ions: Mn 2+ 469 and 470. Both are attached to three protein chains and two water molecules, one of the water molecules are shared by both Mn2+. The protein ligands. Attached to Mn 2+ 469 is: Glu-131, GLu-212 and Glu-220, and the protein ligands attached to Mn 2+ are: Glu-129, His-269 and Glu-357.<ref name="Yamashita"/> <br />
<br />
Unique to glutamine synthetase, unlike other enzymes, is it's "passive site". This refers to the central loop which is formed by a segment of the backbone that extends into the central aqueous cavity. <ref name="Yamashita"/>Unlike other sites in glutamine synthetase under the same conditions, this site is suceptible to proteolysis by four secreated proteases from the V8 protease of ''Staphylococcus aureus''.<ref name="Yamashita"/> [[Image:Passive site.png|thumb|Figure 1: A clear view of glutamine synthetases "passive site".]]<br />
<br />
<br />
<br />
==Classes==<br />
<br />
Glutamine synthetase has been described as having three destinctive types:<ref name="Brown">PMID:7916055 </ref><br />
*Class I (GSI): Genes for this class have only been found in bacteria (eubacteria) and archaea (arhaebacteria. The paper by Kumada ''et. al'' goes into detail on these two.<ref name="Kumada">PMID:8096645 </ref><br />
*Class II (GSII): Genes for this class have only been found in eukaryotes and a few soil-dwelling bacteria.The paper by .... gets into further detail about these bacteria. :<ref>PMID:7916055 </ref><br />
*Class III (GSIII): Genes from this class have only been found in a few bacterial species.It is a hexamer of identical chains. It is much larger (about 700 amino acids) than the GSI (450 to 470 amino acids) or GSII (350 to 420 amino acids) enzymes <ref name="Brown"/>. <br />
<br />
<br />
[[Image:Glutamine-synthesis.jpg|thumb | Figure 2: Two step process of sythesis of glutamine from glutamate, synthesised by glutamine synthesis.]]<br />
<br />
==Function==<br />
<br />
Glutamine synthetase (GS) is an essential enzyme in the cellular nitrogen metabolism and has been found to play a role in both ammonia assimilation and glutamine byosynthesis.<ref name="Kumada"/> It is the only enzyme capable of glutamine synthesis and is required for the two step process synthesizing glutamate to glutamine. The glutamine produced is an essential precursor for purine and pyrimidine synthesis, a modulator of protein turnover or an intermediate for gluconeogenesis and acid-base balance. <ref>He,Youji, Hakvoort,Theodorus, B.M., Kohler,S.Eleonor, Vermeulen,Jacqueline L.M.,Rudi de Waart, D., Theije,Chiel de, Gabrie A.M. ten Have, Van Eijk,Hans M.H., Kunne,Cindy, Labruyere,Wilelmina T., Houten,Sander M., Sokolovic,Mika, Tuijter,Jan M., Deutz,Nicolaas E.P., and Lamers, Wouter H. Glutamine Synthetase in muscle is required for glutamine production druing fasting and extrahepatic ammonia detoxification. The American Society for Biochemistry and Molecular Biology, January 11, 2010 </ref><br />
<br />
<br />
==References==<br />
<references/><br />
<br />
<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr><br />
Rhiannon Khela</div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_174&diff=1064468Sandbox 1742010-03-31T18:43:21Z<p>Andrea Gorrell: </p>
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<div>{{STRUCTURE_2abx | PDB=2abx | SCENE= }}<br />
=Alpha-Bungarotoxin=<br />
Alpha-Bungarotoxin (α-BGT) is a nicotinic cholinergic antagonist that is found within the venom of ''Bungarus multicinctus'', a South-asian snake belonging to a group commonly known as kraits. Belonging to the Elapidae Family, which consist of cobras, kraits, tiger snakes, and mambas, the venom of ''Bungarus multicuntus'' is a complex mixture of many different molecules<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46.</ref> α-BGT belongs to a family of homologous proteins that act as a neurotoxic agent in the venom of these snakes. α-BGT is known to bind irreversibly to the acetylcholine receptor found at the neuromuscular junction, causing respiratory failure, paralysis, and death, as well as play an antagonstic role in binding the α7 nicotinic acetylcholine receptor in the brain.<br />
<br />
=General Structure=<br />
[[Image:figurename.png| left| thumb |Overall structure of Alpha-Bungarotoxin, with all individual residues visible]]<br />
<br />
A large amount of highly homologous snake neurotoxins have been sequenced (>60), and can be grouped into two major classes. Short neurotoxins are between 60-62 amino acids long, and consist of four disulphide bonds, and long neurotoxins - which α-BGT falls under - are between 71-74 amino acids long and contain five <scene name='Sandbox_174/Disulphides/2'>Disulphide Bonds</scene> per subunit. α-BGT contains 74 amino acids, and is one of the major components of ''Bungarus multicuntus'' venom. Chemical modifications of individual residues has shown that no single amino acid is mandatory for binding, signifying the significance of structure, rather than sequence, and the concept of multicontact interaction with the acetylcholine receptor <ref> Karlsson, E. (1979) in Lee,C Y (ed), ''Handbook of Experimental Pharmacology'' Springer-Verlag, Berlin Vol 52, pp 159-212;Low, B.W. (1979) In Lee,c Y (ed). ''Handbook of Experimental Pharmacology'' Springer-Verlag, Berlin, Vol 52, pp 213-257.</ref>. The importance of structure in binding has been tested by Love & Stroud (1986)<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46. </ref> by determining whether the homology and common mode of action of neurotoxins is facilitated by the three-dimensional structure. Using X-ray crystallography at various resolutions, neurotoxins erabutoxin and cobratoxin were compared to that of α-BGT to determine the level of three-dimensional similarity.<br />
<br />
The overall size of the molecule is 40 x 30 x 20 Å, with two outer loops folded toward one another. α-BGT is "flat" enough to contain no hydrophobic core, but does contain a few uncharged sidechain groupings<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46.</ref>.<br />
The protein is a dimer, and consists of two seperate subunits:<br />
<scene name='Sandbox_174/Domain_b/3'>Domain A</scene><br />
<scene name='Sandbox_174/Domain_a/3'>Domain B</scene><br />
<br />
<br />
==Secondary structure & Disulphide bonds==<br />
Hydrogen bods present allow for an antiparallel β-sheet, which is the only secondary structure present and acts to keep the second and third loops roughly parallel<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46.</ref>. The three-loop structure is preserved by four invariant disulphide bridges, which are present in all neurotoxins. The fifth disulphide bridge is located at the end of the second loop, and can be reduced without any effect on the binding affinity of the molecule, while a total loss of toxicity is demonstrated when the remaining disulphides are reduced, producing a random coil structure much different than the native conformation<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46.</ref>. <br />
<br />
The comination of the multiple disulphide bonds and small amount of secondary structure is the cause for the extreme stability of neurotoxins like α-BGT, providing resistance to denaturing forces such as boiling<ref> Tu, A.T. and Hong, B.S (1971) ''J Biol Chem''. '''246''', 2772-2779;Yang, C.C. ''Toxicon'' '''12''', 1-43.</ref> and strong acids<ref>Chiceportiche, R. Rochat, C. Sampien, F. Lazdunski, M. (1972) ''Biochemistry'' '''14''', 2081-2091;Chen, Y.H. Tai, J.C. Huand, W.J. Lau, M.Z. Hung, M.C. Lai, M.D. Yang, J.T. (1982) ''Biochemistry'' '''21''' 2592-2600</ref>. Functionally important residues contained in the extended loops are preserved by the clustering of disulphides near one end of the α-BGT molecule. This is due to an increased amount of flexibility in these extended loops, which is possibly quite important for interaction with acetylcholine receptors.<br />
<br />
=Functions=<br />
Elapidae neurotoxins bind specifically and tightly (with a very high affinity) in a non-covalent manner to the nicotinic acetylcholine receptors in cholinergic synapses of their victims. This prevents normal neurotransmitter-induced channel opening, which in turn blocks postsynaptic membrane depolarization<ref name="main">Love, A.R. and Stroud, R.M. (1986) The Crystal Structure of α-Bungarotoxin at 2.5 Å resolution: Relation to Solution Structure and Binding to Acetylcholine Receptor. ''Protein Eng'' '''1''', 37-46.</ref>, classifying the molecule as a postsynaptic neurotoxin. <br />
==neuromuscular acetylcholine receptor binding==<br />
The irriversible and competitive binding to the acetylcholine receptor by α-BTG can be devastating to an organisms health due to its ability to block the receptors activity. <br />
<br />
==α7 nicotinic acetylcholine receptor binding==<br />
Response to sensory stimuli and seizure genesis has been linked to nicotinic mechanisms<ref>Freedman, R. Wetmore, C. Stromberg, I. Leonard, S. Olsona, L. (1993) Alpha-Bungarotoxin Binding to Hippocampal Interneurons: lmmunocytochemical Characterization and Effects on Growth Factor Expression. ''Journal of Neuroscience'' 13:1965-1975. </ref>, which are mediated by two major classes of receptors: Ganglionic type, and neuromuscular type, which pharmacological analysis of seizure genesis and habituation in the rat brain is thought to be mediated by the latter type <ref> Miner L.L. Collins A.C. (1989) Strain comparison of nicotine-induced seizure sensitivity and nicotinic receptors. ''Pharmacol Biochem Behav'' '''33''', 469-475;Luntz-Leybman, V. Bickford, P. Freedman, R. (1992) Cholinergic gating of response to auditory stimuli in rat hippocampus. ''Brain Res'' '''587''', 130-l-36.</ref>. α-BGT demonstrates this relationship due to its prominent binding in the CA3 region of the hippocampus <ref> Hunt, S.P. Schmidt, J. (1978) The electron microscopic autoradiographic localization of alpha-bungarotoxin binding sites within the central nervous system of the rat: ''Brain Res'' '''142''', 152-l 59;Segal, M. Dudai, Y. Amsterdam, A. (1978) Distribution of cu-bungarotoxin-<br />
binding cholinergic nicotinic receptor in rat brain. ''Brain Res'' '''148''', 105-l 19.</ref>.<br />
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<br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Interleukin-10&diff=1064417Interleukin-102010-03-31T17:08:21Z<p>Andrea Gorrell: </p>
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<div>== '''Interleukin-10''' '''[[2H24]]''' ==<br />
[[Image:2h24.png|left|thumb| Figure 1]]<br />
Interleukin 10 is a ternary complex that requires specific assembly for proper function. The IL-10 complex is composed of IL-10,IL-10R1,IL-10R2. The initial step is the formation of IL-10 and IL-10R1 generating a conformational change that is required for IL-10R2 to be able to associate and form the ternary complex <ref name="ref1">PMID:16982608</ref>. The completed complex activates the [http://en.wikipedia.org/wiki/JAK-STAT_signaling_pathway JAK/STAT signaling pathway]. The completion of the ternary complex is dependent on the conformational changes that occur in the N-Terminus of the helix labelled A. The conformational changes occur when the cIL-10 binds with IL-10R1. There is a positional change of about 1 angstrom at residues between Cys-12 and Leu-46. Due to the <br />
<scene name='Sandbox_165/2h24_backbone/1'>ball and stick of 2h24</scene><br />
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=='''IL-10'''==<br />
Interleukin-10 is in the class [http://en.wikipedia.org/wiki/Cytokine cytokine].<ref name="ref1"/> Interleukin-10 is a very powerful anti-inflammatory cytokine that is most commonly found to be produce by moncytes <ref>PMID:15772682</ref>. IL-10 has the ability to be a immunosupressive as well as a anti-angiogenic this means that it has the ability both promot and inhibit tumors<ref>PMID:16122836</ref>. <br />
There are many types of cytokines that have many funtions such as from antiinflammatory cytokines,cytokine synthesis inhibitory factor and proinflammitory cytokines<ref>PMID:8163935</ref>.<br />
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There are many [http://en.wikipedia.org/wiki/interleukin interleukins] that fall within the cytokine class such as IL-1,IL-2,IL-3,IL-4...IL-31,IL-32,IL-33,IL-3 and IL-35. <br />
{{STRUCTURE_2h24| PDB=2h24| SCENE=Sandbox_165/Interleukin-10/1}}<br />
=Interleukin-10 and Rheumatoid Arthritis=<br />
IL-10 is investigated for its role in patients with [http://en.wikipedia.org/wiki/Rheumatoid_Arthritis Rheumatoid Arthritis] (RA) as well as those with [http://en.wikipedia.org/wiki/Osteoarthritis Osteoarthritis] (OA)<ref>PMID:8163935</ref>.<br />
RA is an autoimmune disorder that affects the [http://en.wikipedia.org/wiki/Synovial_membrane synovial] tissues via chronic synovitis. Chronic synovitis often results in joint destruction due to re-absorption of bone and the distruction of cartilage<ref>PMID:19758192</ref> <ref>PMID:8163935</ref>.<br />
IL-10 is found to spontaneously be produce in synovial tissue of patients with RA and OA but not in normal synovial tissue.The variation in secretion of IL-10 is thought to be at about 75% under the control of the genetics of the individual<ref>PMID:19758192</ref>.When IL-10 is present there is a inhibition of the proinflammatory cytokines, namely TFN-α, IL-1α, IL-1β, IL-6, IL-8 <ref>PMID:1940799</ref>.<br />
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[[Image:Illu_synovial_joint.jpg]]<ref>http://en.wikipedia.org/wiki/Synovial_membrane</ref><br />
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<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr><br />
Shelly Huebert<br />
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== '''References''' ==<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=C-JUN&diff=1062379C-JUN2010-03-30T19:09:38Z<p>Andrea Gorrell: </p>
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<div>Andrew Rebeyka<br />
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<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr><br />
<br />
= C-JUN =<br />
The C-Jun protein belongs the member of the basic region leucine zippere (bZIP) family of transcription factors. All these factors bind to DNA as either homo or heterodimers <ref name="ref1">PMID:8662824</ref>. This union of the two identical molecular units is mediated by each of their leucine zipper domains and subsequently a prerequisite to the binding of their related DNA enhancer elements <ref name="ref1"/>. This prerequisitie is needed as dimerization enables the alpha helical DNA binding domains to be inserted into adjacent grooves of the dyad symmetrical DNA recognition site. this therefore affects the activity of how these proteins are regulated by causing these protein to protein interactions between the leucine zipper domains in addition to the interactions between protein and DNA <ref name="ref1"/>. <br />
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== Introduction ==<br />
C-Jun binds to specific DNA sites either in the homodimer or deterodimer forms with the aid of C-Fos protein <ref>PMID:8662824</ref>. C-Jun is a transcriptional activator <ref>PMID:8662824</ref>. C-jun, with the aid of C-Fos represents a crucial union between normal and uncontrolled cell growth as their combined role in the transduction of afferent growth signals the response of specific genes <ref>PMID:8662824</ref>. <br />
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== Structural Overview ==<br />
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<applet load='1Z82' size='300' frame='true' align='right' caption='1JUN' /><br />
This protein is a dimer that is completely symmetrical (a). It is comprised of coiled coil of two alpha helices (a).<br />
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== Protein Function ==<br />
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== OTHER ==<br />
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=References=<br />
<references/><br />
Junius, F.K., O'Donoghue, Se an I., Niges, M., Weiss, A.S., King, G.F. 1996. High Resolution NMR Solution Structure of Lecuine Zipper Domain of the c-Jun Homodimer. January 4th<br />
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<references/> A Junius, F.K., Mackay, J.P., Bubb, W.A., Jensen, S.A., Weiss, A.S., King, G.F. 2006. Nuclear Magnetic Resonance Characterization of the Jun Leucine Zipper Domain: Unusual Properties of Coiled-Coil Interfacial Polar Residues? <br />
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[[Image:1JUN.png]]<br />
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<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_177&diff=1062369Sandbox 1772010-03-30T18:25:48Z<p>Andrea Gorrell: </p>
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<div>{{STRUCTURE_3es9| PDB=3es9 | SCENE=Sandbox_177/Jmol3es9/1 }}<br />
== '''NADPH-cytochrome P450 oxidoreductase''' ==<br />
<br />
==='''General Information'''===<br />
----<br />
Horecker first identified this protein in 1950 as NADPH-specific cytochrome c reductase, based on his assumption that it was the redox partner for cytochrome c, found in the mitochondria.<ref name="1TSON">Horecker BL. Triphosphopyridine nucleotide-cytochrome ''c'' reductase in liver. J Biol Chem 1950 Apr 1;183(2):593-605</ref> However, studies in the 1960s and later showed that its main function is actually as the redox partner for cytochrome P450 in microsomal electron transport chains, resulting in a name change.<ref name="5TSON"/><ref name="4TSON">Phillips AH, Langdon RG. Hepatic triphosphopyridine nucleotide-cytochrome c reductase: Isolation, characterization, and kinetic studies. J Biol Chem 1962 Aug 1;237:2652-60</ref> Today this protein is known as NADPH-cytochrome P450 oxidoreductase (CYPOR). <br />
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CYPOR is a ~78kDa, multidomain flavoprotein.<ref name="5TSON">PMID:19171935</ref> Containing three co-factors, FAD, FMN and NADPH, this protein is the archetype for the mammalian diflavin-containing enzyme family.<ref name="5TSON"/> Research indicates that the protein, and other FAD/FMN binding proteins, are likely the product of the fusion of two ancestral genes.<ref name="6TSON">PMID:8078947</ref> This would account for the two distinct binding domain areas, FMN and FAD/NADPH, which each provide different functional capabilities to the overall protein.<ref name="6TSON"/><br />
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Regulation of this protein, which is found all tissues to some extent, is largely at the transcriptional level.<ref name="3cTSON">PMID:11306680</ref> The thyroid hormone T3 acts as a hormonal regulator in most cases, while adrenocorticotrophic hormone acts as a regulator in a few specific cases.<ref name="3aTSON">PMID:2495435</ref><ref name="3bTSON">PMID:1737785</ref><br />
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==='''Structure'''===<br />
----<br />
<applet load='3es9' size='275' color='black' frame='true' align='left' scene='Sandbox_177/Cyporplain/2' caption='Figure 1: Highlighting the chains and associated ligands of CYPOR'/><br />
CYPOR is a complex, multidomain protein composed of three chains (<scene name='Sandbox_177/Cyporchaina/2'>A</scene>, <scene name='Sandbox_177/Cyporchainb/1'>B</scene>, <scene name='Sandbox_177/Cyporchainc/1'>C</scene>). It also has three different types of associated ligands; one <scene name='Sandbox_177/Cyporfmn/2'>FMN</scene>, three <scene name='Sandbox_177/Cyporfad/2'>FAD</scene> and two <scene name='Sandbox_177/Cypornadph/2'>NADPH</scene> (Fig 1).<ref name="5TSON"/> The three associated binding domains for these ligand types, a connecting domain and a transmembrane anchor make up the important structural elements of CYPOR (Fig 2). <br />
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The N-terminus of CYPOR consists of a single alpha-helix composed of 25 amino acids that functions as a transmembrane anchor (~6kDa), holding the protein in the endoplasmic reticulum.<ref name="5TSON"/><ref name="10aTSON">PMID:18630181</ref> The remaining, soluble ~66kDa portion of the protein, responsible for reducing cytochrome P450, consists of three binding domains for the ligands involved in the electron transport chain.<ref name="5TSON"/> The FMN binding domain is composed of the first 170 residues of the soluble region, which are very similar to those of flavodoxin, another FMN binding protein.<ref name="5TSON"/> The FAD and NADPH binding domains are located closer to the C-terminus, and are very similar to the FAD domain in ferredoxin-NADP<sup>+</sup> oxidoreductase, both in terms of sequence and structure.<ref name="5TSON"/><br />
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Between the FMN and FAD/NADPH bind domains is a connecting domain, which is a highly flexible random coil.<ref name="5TSON"/> The hinge region is composed of 12 residues from <scene name='Sandbox_177/Cyporhinge/2'>Gly232 to Arg243</scene>, and is highly conserved among most known CYPOR proteins, including those found in humans, rats and even yeast.<ref name="5TSON"/> This section is presumed to be responsible for the relatively increased mobility of the FMN domain, changes to conformation and the relative orientation of the binding domains.<ref name="5TSON"/> Studies that examined the rate of electron transfer within CYPOR seem to confirm this, as electron transfer rate appears to decrease proportionally to increases in the viscosity of the fluid medium it is in.<ref name="5TSON"/> When residues within the the hinge are mutated so it is no longer flexible, studies have found that CYPOR cannot effectively transfer electrons to cytochrome P450, unless there is a high electron pool available.<ref name="5TSON"/> This indicates that without the hinge movement electrons are not able to be efficiently moved from FAD to FMN, decreasing the reductase capabilities of CYPOR.<ref name="5TSON"/> These surface proteins are<br />
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==='''Function'''===<br />
----<br />
[[Image:CPR chargepair.gif|thumb|right|300px|Figure 2: Electrostatic charge pairing between Cyt P450 and the FMN binding domain induces the interaction between CYPOR and Cyt P450.]]<br />
''In vivo'' CYPOR is believe to alternate between a one and a three electron reduced form. While the 1 electron form is fairly stable, forming a neutral blue semiquinone, it is the hydroquinone, or 3 electron form, that is able to donate electrons to the desired redox partners.<br />
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As part of the microsomal electron transport system, CYPOR moves electrons from:<br />
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:::'''<span style="background-color:#FFA07A">NADPH</span> → <span style="background-color:#F0E68C">FAD</span> → <span style="background-color:#98FB98">FMN</span> → <span style="background-color:#AFEEEE">Cytochrome P450</span>''' <br />
<br />
Specifically a hydride anion is moved from NADPH to the FAD.<ref name="5TSON"/> The two electrons are then individually passed to FMN, in a process that is believed to be conformationally gated.<ref name="5TSON"/> As previously discussed in the structure section, this belief is based upon the fact that electrons do not appear to be able to be transferred from FAD to FMN unless the two ligands are in close proximity.<ref name="5TSON"/> The protein accomplishes this by undergoing a conformational change, believed to occur because of the flexibility of the hinge domain, which brings the flavin isoalloxazine rings of FMN and FAD into close proximity to one another.<ref name="5TSON"/> In this closed conformation van der Waals forces help hold the ligands together, allowing for efficient electron movement.<ref name="5TSON"/> However, for CYPOR to transfer the electrons, again one at a time, from FMN to cytochrome P450, CYPOR cannot be in a closed conformation because it prevents cytochrome P450 from being able to access FMN.<ref name="5TSON"/> As a result CYPOR must undergo another conformational change so it is in an open conformation allowing the necessary surface residues on the FMN binding domain to form interactions with cytochrome P450 for electron transfer to occur (Fig 2).<ref name="5TSON"/> These surface residues have been found to have an increased number of carboxyl containing amino acids (Aspartate and glutamate), which gives this area a negative charge (Fig 2).<ref name="7aTSON">PMID:1929397</ref><ref name="7bTSON">PMID:3016501</ref> The carboxyl groups can then bind basic residues like leucine found on cytochrome P450 to correctly orient the two proteins for electron transfer.<ref name="7aTSON"/><ref name="7bTSON"/> Additionally, cytochrome P450 can have an induced dipole moment across it, with a partial positive charge occurring on the side of the protein where the internal heme is closest to the surface of the protein (Fig 2). <ref name="7aTSON"/><ref name="7bTSON"/> The partial positive charge interacting with the previously mentionned acidic residues of CYPOR is thought to help solidify the interaction between CYPOR and cytochrome P450 in the best orientation for electron transfer.<ref name="7aTSON"/><ref name="7bTSON"/><br />
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This reduction of cytochrome P450 allows it to function in biosynthesis and biodegradation pathways of a variety of endogenous and foreign hydrophobic substrates, including drugs and steroids.<ref name="5TSON"/><ref name="2TSON">PMID:7743131</ref> Cytochrome b5, cytochrome c and heme oxygenase can also receive electrons from CYPOR.<ref name="5TSON"/> In these cases CYPOR is functioning in the heme degradation pathway, or with monooxygenase and/or 7-dehydrocholesterol reductase in sterol synthesis.<ref name="5TSON"/><br />
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==='''Medical Significance'''===<br />
----<br />
'''Cancer''' - Studies have shown that the reductase activity of CYPOR is capable of activating anticancer prodrugs.<ref name="5TSON"/><ref name="8TSON">PMID:2228151</ref> Elevated expression of CYPOR has been found to increase the sensitivity of cancerous cells to certain anticancer drugs like tirapazamine.<ref name="8TSON"/> This makes it a potential target for anticancer research and therapy.<br />
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'''Embryology & Development''' - CYPOR is believed to play a key role in the spatial and temporal expression of various signaling factors that are key in establishing correct embryogenesis and development pathways.<ref name="9TSON">PMID:11742006</ref> Studies with mice have shown that CYPOR is critical for mice embryos to progress into and past mid-gestation, as embryos lacking both CYPOR alleles did not survive past day 13.5 of gestation. <ref name="9TSON"/> Even mice, who were heterozygotes for the allele, were found to have a decreased survival rate after 2 weeks of gestation.<ref name="9TSON"/> In humans, while deficiencies in CYPOR are not necessarily lethal, they do have some severe side effects, including disordered steroidogenesis and Antley-Bixler syndrome (ABS).<ref name="10aTSON"/><ref name="10bTSON">PMID:16467261</ref> ABS is associated with urogenital defects (ie: ambiguous genitalia), cranial abnormalities (ie: brachycephaly) and skeletal defects (ie: bowed femurs, narrow ribcage and club feet), often due to disordered steroidogenesis.<ref name="10aTSON"/><ref name="10bTSON"/> Individuals with ABS and/or disordered steroidogenesis may have mutations in one or both alleles for CYPOR, although some cases are associated with mutations in another gene, fibroblast growth factor receptor 2 gene.<ref name="10bTSON"/><ref name="10aTSON"/><br />
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==References==<br />
<references/><br />
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<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=SecA&diff=1061470SecA2010-03-26T19:35:08Z<p>Andrea Gorrell: </p>
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<div>=Introduction=<br />
The [http://www.nature.com/nature/journal/v455/n7215/full/nature07335.html SecA] ATPase SecA drives the post-translational translocation of proteins through the SecY channel in the bacterial inner membrane. SecA is a dimer that can dissociate into monomers under certain conditions. Many bacterial proteins are transported post-translationally across the inner membrane by the Sec machinery, which consists of two essential components (1-4). One is the SecY complex, which forms a conserved heterotrimeric protein-conducting channel in the inner membrane.<ref name=journal1>PMID:15618215</ref> The other is SecA, a cytoplasmic ATPase, which "pushes" substrate polypeptide chains through the SecY channel.<ref name=journal1/> http://journal.shouxi.net/qikan/article.php?id=418668<br />
{{ STRUCTURE_3jv2 | PDB=3jv2 | SCENE=Sandbox_158/Scene_1/1 }}<br />
=Structure=<br />
[http://www.nature.com/nature/journal/v455/n7215/full/nature07335.html SecA] SecA consists of two RecA-like nucleotide-binding domains (NBD1 and NBD2), which bind the nucleotide between them, a polypeptide-cross-linking domain (PPXD), a helical scaffold domain (HSD) and a helical wing domain (HWD)<ref name=journal2>PMID:18923516</ref> Although several crystal structures of isolated SecA have been determined, the function of the different domains and the mechanism by which SecA moves polypeptides through the channel remain unknown. Disulphide cross-linking experiments suggest that SecA binds by its NBD1 domain to a non-translocating SecY copy, and moves the polypeptide chain through a neighbouring SecY molecule6. These and other experiments indicate that SecA functions as a monomer during translocation<ref name=journal2/>but the issue remains controversial.<ref name=journal2/><br />
Here we report crystal structures of SecA bound in an intermediate state of nucleotide hydrolysis to the SecY channel. The structures suggest mechanisms for how the channel is opened and prepared for the arrival of a translocation substrate, and how SecA moves polypeptides through the channel. http://www.nature.com/nature/journal/v455/n7215/full/nature07335.html<br />
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This is the active site <scene name='Sandbox_158/Scene_1/3'>ADP</scene> with surrounding amino acids shown.<br />
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==Structure Determination Of SecA-SecY Complexes==<br />
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[http://www.nature.com/nature/journal/v455/n7215/full/nature07335.html SecA] Crystallized complexes containing Bacillus subtilis SecA without its non-essential carboxy-terminal domain, and either Thermotoga maritima SecYE or Aquifex aeolicus SecYEG. These crystals diffracted X-rays to a maximum resolution of 6.2 Å and 7.5 Å, respectively. A higher resolution data set (4.5 Å) was obtained for a complex in which both partners were from T. maritima and the SecYEG complex was seleno-methionine (Se-Met) derivatized. All complexes were crystallized in the detergent Cymal-6 in the presence of ADP and BeFx. The structure of the complex of B. subtilis SecA and T. maritima SecYE was determined by molecular replacement with a B. subtilis SecA structure<ref name=journal2/> and served as an initial model for the other complexes. The building of a 4.5 Å resolution model of the T. maritima SecA–SecY complex was facilitated by the Se-Met positions (Supplementary Fig. 1), and by the high quality of the phases, leading to an electron density map that allowed the identification of large amino acid side chains (Fig. 1a and Supplementary Fig. 2). Model building also took into account conserved interactions between amino acids in previously determined SecA and SecY structures5<ref name=journal2/>(sequence alignments are shown in Supplementary Figs 3 and 4). The final structure was refined to Rwork and Rfree factors of 27.9% and 30.3% (Table 1), respectively, and was used for all interpretations. It comprises all residues of SecA and most residues of SecYEG. No model could be built for the periplasmic loop between TM1 and TM2a of SecY (residues 42–61), as well as for residues of some termini (SecY residues 1–7 and 424–431; SecE residues 1–9; SecG residues 1–8 and 74–76). Furthermore, there are uncertainties about the tip of the loop between TM6 and TM7 (residues 240–254). An ADP–BeF3- complex was modelled into the electron density observed in the nucleotide-binding pocket of SecA (Supplementary Fig. 5). <br />
<br />
'''For a figure of the SecA-SecY complex click here''' [http://www.nature.com/nature/journal/v455/n7215/images/nature07335-f1.2.jpg SecA-SecY Complex]<br />
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a, Stereo view of a A-weighted, phase combined, NCS averaged, and B-factor sharpened 2Fo - Fc electron density map (contoured at 1). The view of the lateral gate of SecY is shown, with the C-trace of SecY in grey, SecE in red, SecG in green and SecA in blue. b, Cartoon of the complex viewed from the side. The lines indicate the membrane boundaries. c, As in b, but viewed from the cytoplasm. d, The two-helix finger of SecA inside the cytoplasmic funnel of SecY. TM2b and TM8, as well as the tip of the 6–7 loop, are shown as cartoons for clarity. Plug residues are coloured in orange. e, As in d, but shown from the back.<ref name=journal2/><br />
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==Function==<br />
[http://journal.shouxi.net/qikan/article.php?id=418668 SecA] SecA interacts not only with the SecY<ref name=journal1/> channel but also with acidic phospholipids (9-11) and with both the signal sequence and the mature part of a substrate protein<ref name=journal1/>. It also binds the chaperone SecB, which ushers some precursor proteins to SecA<ref name=journal1/>. When associated with the SecY complex, SecA undergoes repeated cycles of ATP-dependent conformational changes, which are linked to the movement of successive segments of a polypeptide chain through the channel<ref name=journal1/>. However the mechanism employed by SecA to translocate substrates polypeptide chains through the SecY channel remains largely unknown.<br />
An important issue concerning the function of SecA is its oligomeric state during translocation. SecA is a dimer in solution<ref name=journal1/>, and previous work argued that this is its functional state<ref name=journal1/>. An x-ray structure of Bacillus subtilis SecA also indicates the existence of a dimer<ref name=journal1/>. However, recent evidence raises the possibility that SecA might actually function as a monomer; in solution, SecA dimers are in rapid equilibrium with monomers<ref name=journal1/>. Although the equilibrium favors dimers, it is shifted almost completely toward monomers in the presence of membranes containing acidic phospholipids or upon binding to the SecY complex<ref name=journal1/>. A synthetic signal peptide had a similar effect, although this result is controversial<ref name=journal1/>. A monomeric derivative of SecA containing six point mutations retained some in vitro translocation activity<ref name=journal1/>, but the low level of translocation precluded any firm conclusion. In addition, the previous results do not exclude models in which SecA cycles between monomeric and oligomeric states during the translocation of a polypeptide chain<ref name=journal1/>. Most importantly, the functional oligomeric state of SecA in vivo remains to be established. http://journal.shouxi.net/qikan/article.php?id=418668<br />
<br />
==Expression of the Bacillus subtilis secA Gene==<br />
In Bacillus subtilis, the secretion of extracellular proteins strongly increases upon transition from exponential growth to the stationary growth phase. It is not known whether the amounts of some or all components of the protein translocation apparatus are concomitantly increased in relation to the increased export activity. In this study, we analyzed the transcriptional organization and temporal expression of the secA gene, encoding a central component of the B. subtilis preprotein translocase. We found that secA and the downstream gene (prfB) constitute an operon that is transcribed from a vegetative (A-dependent) promoter located upstream of secA. Furthermore, using different independent methods, we found that secA expression occurred mainly in the exponential growth phase, reaching a maximal value almost precisely at the transition from exponential growth to the stationary growth phase. Following to this maximum, the de novo transcription of secA sharply decreased to a low basal level. Since at the time of maximal secA transcription the secretion activity of B. subtilis strongly increases, our results clearly demonstrate that the expression of at least one of the central components of the B. subtilis protein export apparatus is adapted to the increased demand for protein secretion. Possible mechanistic consequences are discussed.<ref name=journal3>PMID:9882663</ref> http://jb.asm.org/cgi/content/abstract/181/2/493<br />
=References=<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Sandbox_200&diff=1061469Sandbox 2002010-03-26T19:34:14Z<p>Andrea Gorrell: </p>
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<div><table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr><br />
=Example Page=<br />
[[Title text-here's my first stab]]<br />
Text on the page <ref> This is my reference </ref><br />
{{STRUCTURE_1tuu| PDB=1tuu | SCENE=Sandbox_200/Scenea/1}}<br />
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==Adenylosuccinate Synthetase==<br />
Enzyme shown in ''Escherichia coli'' adenylosuccinate synthetase. <br />
<scene name='Sandbox_200/Scene1/7'>Ball-and-stick view</scene><br />
the ligands bound in the second acitve site are <scene name='Sandbox_200/Amp/1'>AMP and PIS</scene> a hydrolyzed version of gamma-thio ATP, the hydolysis a consequence of crystallization.<br />
Image of GroEL/GroES<br />
[[Image:GroELGroES.png|thumb]]<br />
[[Image:2HU4monomer.png|thumb|2HU4 monomer showing b-sheets]]<br />
==Reaction catalyzed==<br />
ATP + acetate -> acetyl phosphate + ADP<br />
<scene name='Sandbox_200/Scene1/6'>focus on ligands</scene><br />
=References=<br />
Follow referencing format as prefered by Proteopedia (see Citing Literature References Section in [[Help:Editing]] page)<br />
<references/></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=File:2HU4monomer.png&diff=1061466File:2HU4monomer.png2010-03-26T19:32:27Z<p>Andrea Gorrell: </p>
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<div></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=File:Collagen.png&diff=1060983File:Collagen.png2010-03-25T22:40:54Z<p>Andrea Gorrell: </p>
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<div></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Glycerol-3-Phosphate_Dehydrogenase&diff=1060953Glycerol-3-Phosphate Dehydrogenase2010-03-25T22:04:05Z<p>Andrea Gorrell: </p>
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<div>Indu Toora <br />
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'''Glycerol 3-Phosphate Dehydrogenase'''<br />
<applet load='1Z82' size='300' frame='true' align='right' caption='Glycerol 3-Phosphate Dehydrogenase' /><br />
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== Introduction ==<br />
===Structure===<br />
[[Image:FINAL.png]]<br />
===Function===<br />
====Metabolism====<br />
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===Diseases===<br />
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<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=File:FINAL.png&diff=1060951File:FINAL.png2010-03-25T22:02:24Z<p>Andrea Gorrell: </p>
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<div></div>Andrea Gorrellhttps://proteopedia.org/index.php?title=Shwachman-Bodian-Diamond_Syndrome_Protein&diff=1060925Shwachman-Bodian-Diamond Syndrome Protein2010-03-25T21:33:55Z<p>Andrea Gorrell: </p>
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<div><table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr><br />
Simmi Parhar<br />
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= '''Shwachman-Bodian-Diamond Syndrome Protein''' =<br />
== Overview ==<br />
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The human Shwachman-Bodian-Diamond syndrome(SBDS) protein belongs to a very conserved family of proteins of unknown function; orthologues found in Archaea, as well as plants and other eukaryotes <ref name="one">PMID:15701631</ref><ref name="two">PMID:15701634</ref>. Evidence has been provided that the SBDS protein orthologues may play a role in RNA metabolism <ref>PMID:15701631</ref>. Two groups of SBDS orthologues have been identified. Archaea, animals, and fungi have SBDS proteins with approximately 250 amino acid residues. However, SBDS protein of plants and protists has the C-terminal extensions around 100 to 250 amino acid residues <ref>PMID:19121363</ref>. The resolution of the Archaeoglobulus fulgidus SBDS protein orthologue is at a resolution of 1.9 angstroms; showcasing a three domain architecture <ref>PMID: 15701631</ref>. The domain that is the most targeted for disease mutations is the <scene name='Sandbox_178/Sbds/3'>N-terminal domain</scene>; containing a mixed alpha/beta fold. The central domain has a three-helical bundle, and the C-terminal domain has a ferredoxin-like fold <ref>PMID:15701631</ref>.<br />
==Structure==<br />
{{STRUCTURE_1t95 | PDB=1T95 | SCENE=Sandbox_178/Sbds/4}}<br />
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[[Image:1t96fig.png]]<br />
=References=<br />
<references/></div>Andrea Gorrell