PDBsum entry 1sir

Oxidoreductase

PDB id: 1sir

Contents

Protein chain

390 a.a. *

Ligands

FAD

NBC

Waters ×77

* Residue conservation analysis

PDB id:

1sir

Name:

Oxidoreductase

Title:

The crystal structure and mechanism of human glutaryl-coa dehydrogenase

Structure:

Glutaryl-coa dehydrogenase. Chain: a. Synonym: gcd. Ec: 1.3.99.7

Source:

Homo sapiens. Human. Organism_taxid: 9606. Strain: bacterial:bl21

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.60Å R-factor: 0.187 R-free: 0.240

Authors:

M.Wang,Z.Fu,R.Paschke,S.L.Goodman,F.E.Frerman,J.J.Kim

Key ref:

Z.Fu et al. (2004). Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions. Biochemistry, 43, 9674-9684. PubMed id: 15274622 DOI: 10.1021/bi049290c

Date:

01-Mar-04 Release date: 07-Sep-04

Protein chain

Q92947  (GCDH_HUMAN) -  Glutaryl-CoA dehydrogenase, mitochondrial from Homo sapiens

Seq: 438 a.a.

Struc: 390 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.8.6 - glutaryl-CoA dehydrogenase (ETF).
• Reaction: glutaryl-CoA + oxidized [electron-transfer flavoprotein] + 2 H⁺ = (2E)- butenoyl-CoA + reduced [electron-transfer flavoprotein] + CO2

glutaryl-CoA (Bound ligand (Het Group name = NBC) matches with 89.83% similarity) + oxidized [electron-transfer flavoprotein] + 2 × H(+) = (2E)- butenoyl-CoA + reduced [electron-transfer flavoprotein] + CO2

• Cofactor: FAD

FAD (Bound ligand (Het Group name = FAD) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/bi049290c

Biochemistry 43:9674-9684 (2004)

PubMed id: 15274622

Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions.

Z.Fu, M.Wang, R.Paschke, K.S.Rao, F.E.Frerman, J.J.Kim.

ABSTRACT

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.