1sir
The Crystal Structure and Mechanism of Human Glutaryl-CoA Dehydrogenase
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OverviewOverview
Acyl-CoA dehydrogenases (ACDs) are a family of flavoenzymes that, metabolize fatty acids and some amino acids. Of nine known ACDs, glutaryl-CoA dehydrogenase (GCD) is unique: in addition to the, alpha,beta-dehydrogenation reaction, common to all ACDs, GCD catalyzes, decarboxylation of glutaryl-CoA to produce CO(2) and crotonyl-CoA. Crystal, structures of GCD and its complex with 4-nitrobutyryl-CoA have been, determined to 2.1 and 2.6 A, respectively. The overall polypeptide folds, are the same and similar to the structures of other family members. The, active site of the unliganded structure is filled with water molecules, that are displaced when enzyme binds the substrate. The structure strongly, suggests that the mechanism of dehydrogenation is the same as in other, ACDs. The substrate binds at the re side of the FAD ring. Glu370 abstracts, the C2 pro-R proton, which is acidified by the polarization of the, thiolester carbonyl oxygen through hydrogen bonding to the 2'-OH of FAD, and the amide nitrogen of Glu370. The C3 pro-R proton is transferred to, the N(5) atom of FAD. The structures indicate a plausible mechanism for, the decarboxylation reaction. The carbonyl polarization initiates, decarboxylation, and Arg94 stabilizes the transient crotonyl-CoA anion., Protonation of the crotonyl-CoA anion occurs by a 1,3-prototropic shift, catalyzed by the conjugated acid of the general base, Glu370. A tight, hydrogen-bonding network involving gamma-carboxylate of the enzyme-bound, glutaconyl-CoA, with Tyr369, Glu87, Arg94, Ser95, and Thr170, optimizes, orientation of the gamma-carboxylate for decarboxylation. Some pathogenic, mutations are explained by the structure. The mutations affect protein, folding, stability, and/or substrate binding, resulting in, inefficient/inactive enzyme.
DiseaseDisease
Known disease associated with this structure: Glutaricaciduria, type I OMIM:[608801]
About this StructureAbout this Structure
1SIR is a Single protein structure of sequence from Homo sapiens with FAD and NBC as ligands. Active as Glutaryl-CoA dehydrogenase, with EC number 1.3.99.7 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions., Fu Z, Wang M, Paschke R, Rao KS, Frerman FE, Kim JJ, Biochemistry. 2004 Aug 3;43(30):9674-84. PMID:15274622
Page seeded by OCA on Mon Nov 12 19:14:21 2007