Structures of isobutyryl-CoA dehydrogenase and enzyme-product complex: comparison with isovaleryl- and short-chain acyl-CoA dehydrogenases.
The acyl-CoA dehydrogenases are a family of mitochondrial flavoproteins involved in the catabolism of fatty and amino acids. Isobutyryl-CoA dehydrogenase (IBD) is involved in the catabolism of valine and catalyzes the conversion of isobutyryl-CoA to methacrylyl-CoA. The crystal structure of IBD with and without substrate has been determined to 1.76-A resolution. The asymmetric unit contains a homotetramer with substrate/product bound in two monomers. The overall structure of IBD is similar to those of previously determined acyl-CoA dehydrogenases and consists of an NH2-terminal alpha-helical domain, a medial beta-strand domain and a C-terminal alpha-helical domain. The enzyme-bound ligand has been modeled in as the reaction product, methacrylyl-CoA. The location of Glu-376 with respect to the C-2-C-3 of the bound product and FAD confirms Glu-376 to be the catalytic base. IBD has a shorter and wider substrate-binding cavity relative to short-chain acyl-CoA dehydrogenase, permitting the optimal binding of the isobutyryl-CoA substrate. The dramatic lateral expansion of the binding cavity seen in isovaleryl-CoA dehydrogenase is not observed in IBD. The conserved tyrosine or phenylalanine that defines a side of the binding cavity in other acyl-CoA dehydrogenases is replaced by a leucine (Leu-375) in the current structure. Substrate binding changes the position of some residues lining the binding pocket as well as the position of the loop containing the catalytic glutamate and subsequent helix. Three clinical mutations have been modeled to the structure. The mutations do not affect substrate binding but instead appear to disrupt protein folding and/or stability.
Battaile
Kevin P
KP
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Nguyen
Tien V
TV
Vockley
Jerry
J
Kim
Jung-Ja P
JJ
D000595:Amino Acid Sequence; D001665:Binding Sites; D044926:Butyryl-CoA Dehydrogenase / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D050769:Isovaleryl-CoA Dehydrogenase; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D044925:Oxidoreductases Acting on CH-CH Group Donors; D044926:Butyryl-CoA Dehydrogenase; D050769:Isovaleryl-CoA Dehydrogenase; C038808:2-methylacyl-CoA dehydrogenase