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Pyruvate decarboxylase: Difference between revisions

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<StructureSection load='1zpd' size='450' side='right' scene='' caption='Pyruvate decarboxylate complex with phosphono ester, citrate and Mg+2 ion (green) (PDB code [[1zpd]])'>
==The Enzyme Pyruvate Decarboxylase==
==The Enzyme Pyruvate Decarboxylase==


[[Image:Pyruvate decarb 1.jpg]]
[[Image:Pyruvate decarb 1.jpg|left|450px|thumb]]


'''Image 1: Reaction catalyzed by pyruvate decarboxylase:
'''Image 1: Reaction catalyzed by pyruvate decarboxylase:
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==Structure==
==Structure==
{{STRUCTURE_1zpd |  PDB=1zpd  |  SCENE=  }}
Pyruvate decarboxylase is a homotetramer. Each identical subunit consists of approximately alternating α-helices and β-sheets, and 2 domains exist within each 60kDa <scene name='Ken_Engle_SANDBOX/Subunit/7'>subunit</scene>. This means its SCOP category is alpha and beta protein <ref>PMID:9685367</ref>. Being a homotetramer, pyruvate PDC has 4 identical <scene name='Ken_Engle_SANDBOX/Active_site/3'>active sites</scene> that are green surrounding the ligands when the previous link is selected.  
Pyruvate decarboxylase is a homotetramer. Each identical subunit consists of approximately alternating α-helices and β-sheets, and 2 domains exist within each 60kDa <scene name='Ken_Engle_SANDBOX/Subunit/7'>subunit</scene>. This means its SCOP category is alpha and beta protein <ref>PMID:9685367</ref>. Being a homotetramer, pyruvate PDC has 4 identical <scene name='Ken_Engle_SANDBOX/Active_site/3'>active sites</scene> that are green surrounding the ligands when the previous link is selected.  


==Active Site==
==Active Site==


The active site of PDC in Zymomonas mobilis consists of Glu50, Glu 473, Asp27, and His114 <ref>PMID: 20099870 </ref>. Hydrogen bonding occurs between the substrate and Asp27, His114, and Thr72. Yeast active site residues are similar. In the catalytic step of the reaction mechanism, <scene name='Ken_Engle_SANDBOX/Glu_473/2'>Glu 473</scene>, shown in red, donates a proton to the pyruvate. The scene shows the close proximity of this residue to the pyruvate. The negative charge of the Glu residue following the protonation of the substrate leads to the destabilization of the pyruvate carboxylate group. Next the carboxyl group leaves. Following decarboxylation in the final step of the mechanism, release of acetaldehyde, a proton is transferred to the Glu473 residue from a cofactor. After the protonation in a concerted step, a water molecule donates a proton to the substrate while receiving a proton from Glu473. As the proton is taken from the substrate, the electrons move to form a carbonyl, which leads to the release of the acetaldehyde<ref>PMID: 20099870 </ref>.


Regulation==
 
The <scene name='40/401493/Active_site/1'>active site</scene> of PDC consists of Glu 477, Asp28,  His114, and His 115 as well as the thiamine diphosphate cofactor. Hydrogen bonding occurs between the substrate and Asp28, His114, and Thr73.  In the catalytic step of the reaction mechanism, <scene name='Ken_Engle_SANDBOX/Glu_473/2'>Glu 473</scene>, shown in red, donates a proton to the pyruvate. The scene shows the close proximity of this residue to the pyruvate. The negative charge of the Glu residue following the protonation of the substrate leads to the destabilization of the pyruvate carboxylate group. Next the carboxyl group leaves, using thyiamine diphosphate as an electron sink (described below). Following decarboxylation in the final step of the mechanism, release of acetaldehyde, a proton is transferred to the Glu477 residue from a cofactor. After the protonation in a concerted step, a water molecule donates a proton to the substrate while receiving a proton from Glu477. As the proton is taken from the substrate, the electrons move to form a carbonyl, which leads to the release of the acetaldehyde.
 
==Regulation==


PDC is regulated by substrate activation. This means that if substrate is not present in the pathway, the protein will be "off." The residue that is bound to start a cascade of events resulting in the activation of the enzyme is <scene name='Ken_Engle_SANDBOX/Regulation_site/3'>C 221</scene><ref>PMID: 11412092 </ref> which is highlighted in pink in the scene. This process allows the enzyme to be on when its function is necessary and off when it would not be catalyzing the reaction even if it were on.
PDC is regulated by substrate activation. This means that if substrate is not present in the pathway, the protein will be "off." The residue that is bound to start a cascade of events resulting in the activation of the enzyme is <scene name='Ken_Engle_SANDBOX/Regulation_site/3'>C 221</scene><ref>PMID: 11412092 </ref> which is highlighted in pink in the scene. This process allows the enzyme to be on when its function is necessary and off when it would not be catalyzing the reaction even if it were on.
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==ThDP an Important Cofactor==
==ThDP an Important Cofactor==


Thiamine diphosphate (ThDP) is an important cofactor in the pyruvate, acetaldehyde reaction. The <scene name='Ken_Engle_SANDBOX/Diphosphate_groups/2'>orange diphosphate group</scene> of this cofactor can be seen in this scene near the four active sites though they are hidden in other scenes by the ligand, pyruvate. ThDP actually binds the substrate during the first step of the reaction at C2 of the pyruvate. It is this ThDP that changes the environment of the active site which leads to the protonation or deprotonation of Glu473. When ThDP is not bound, the active site is not even open to bind pyruvate. When it binds, it causes a conformational change, moving Glu473 in such a way that forms a pocket for pyruvate’s methyl group<ref>PMID: 20099870 </ref>.
Thiamine diphosphate (ThDP) is an important cofactor in alpha decarboxylation reactions. The structure of ThDP is <scene name='40/401493/Bent_tpp/1'>bent</scene> when bound to the protein. This kink brings the 4'N of ThDP in close enough proximity to C2 to <scene name='40/401493/Deprotonation/2'>deprotonate</scene> it, forming a reactive ylid <ref>PMID:PMID: 8974393</ref>. Glutamic acid 51 on the other side of ThDP forms a <scene name='40/401493/Glu51_h_bond_to_thdp/1'>hydrogen bond</scene> with ThDP to increase the basicity of 4'N.  In the decarboxylation reaction, <scene name='40/401493/Tpp_c2/1'>C2</scene> of ThDP is deprotonated, and attacks C2 of the pyruvate (this structure has pyruvamide instead of pyruvate), resulting in a <scene name='40/401493/Tpp_c2_to_c2/1'>covalent bond</scene> between ThDP and the pyruvate.  This allows the ThDP to act as an electron sink for the decarboxylation reaction.
</StructureSection>
__NOTOC__
 
==3D structures of pyruvate decarboxylase==
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
{{#tree:id=OrganizedByTopic|openlevels=0|


*Pyruvate decarboxylase
**[[2wva]], [[2wvg]], [[2wvh]], [[1zpd]] - ZmPyD – ''Zymomonas mobilis''<br />
**[[2vk4]], [[6efg]] – KlPyD – ''Kluveromyces lactis''<br />
**[[2vbi]] – PyD – ''Acetobacter pasteurianus''<br />
**[[3mve]] - VvPyD - ''Vibrio vulnificus''<br />
**[[5euj]] - PyD - ''Zymobacter palmae''<br />
*Pyruvate decarboxylase complex
**[[1pvd]], [[1pyd]], [[1qpb]] - yPyD + ThDP - yeast<br />
**[[2w93]] - yPyD (mutant) + ThDP <br />
**[[2vk1]] - yPyD (mutant) + pyruvic acid + ThDP<br />
**[[2vk8]] - yPyD (mutant) + hydroxypropanoic acid + ThDP<br />
**[[2vjy]] – KlPyD + substrate analog <br />
**[[6efh]] - KlPyD + ThDP<br />
**[[4cok]] - PyD + ThDP – ''Glucanacetobacter diazotrophicus''<br />
**[[3our]] - VvPyD + EIIA<br />
**[[5npu]] - PyD + TPP - synthetic<br />
**[[3oe1]], [[4zp1]], [[5tma]] – ZmPyD (mutant) + ThDP derivative<br />
}}
==Additional Resources==
==Additional Resources==
For additional information, see: [[Carbohydrate Metabolism]]
For additional information, see: [[Carbohydrate Metabolism]]
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<references />
<references />
[[Category:Topic Page]]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Ken Engle, David Canner, Michal Harel, Alexander Berchansky, Joel L. Sussman, Ann Taylor
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