Crystal structure of 4-hydroxybutyryl-CoA dehydratase: radical catalysis involving a [4Fe-4S] cluster and flavin.
Dehydratases catalyze the breakage of a carbon-oxygen bond leading to unsaturated products via the elimination of water. The 1.6-A resolution crystal structure of 4-hydroxybutyryl-CoA dehydratase from the gamma-aminobutyrate-fermenting Clostridium aminobutyricum represents a new class of dehydratases with an unprecedented active site architecture. A [4Fe-4S](2+) cluster, coordinated by three cysteine and one histidine residues, is located 7 A from the Re-side of a flavin adenine dinucleotide (FAD) moiety. The structure provides insight into the function of these ubiquitous prosthetic groups in the chemically nonfacile, radical-mediated dehydration of 4-hydroxybutyryl-CoA. The substrate can be bound between the [4Fe-4S](2+) cluster and the FAD with both cofactors contributing to its radical activation and catalytic conversion. Our results raise interesting questions regarding the mechanism of acyl-CoA dehydrogenases, which are involved in fatty acid oxidation, and address the divergent evolution of the ancestral common gene.
Martins
Berta M
BM
Max-Planck-Institut Biochemie, Strukturforschung, 82152 Martinsried, Germany. martins@biochem.mpg.de
Dobbek
Holger
H
Cinkaya
Irfan
I
Buckel
Wolfgang
W
Messerschmidt
Albrecht
A
D002384:Catalysis; D020134:Catalytic Domain; D003013:Clostridium / Q000201:enzymology / Q000235:genetics; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry; D006836:Hydro-Lyases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000737:chemistry; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D055672:Static Electricity; D013455:Sulfur / Q000737:chemistry
D005609:Free Radicals; D005182:Flavin-Adenine Dinucleotide; D013455:Sulfur; D007501:Iron; C066370:4-hydroxybutyryl-CoA dehydratase; D006836:Hydro-Lyases