Structural and mechanistic similarities of 6-phosphogluconate and 3-hydroxyisobutyrate dehydrogenases reveal a new enzyme family, the 3-hydroxyacid dehydrogenases.
Rat 3-hydroxyisobutyrate dehydrogenase exhibits significant amino acid sequence homology with 6-phosphogluconate dehydrogenase, D-phenylserine dehydrogenase from Pseudomonas syringae, and a number of hypothetical proteins encoded by genes of microbial origin. Key residues previously proposed to have roles in substrate binding and catalysis in sheep 6-phosphogluconate dehydrogenase are highly conserved in this entire family of enzymes. Site-directed mutagenesis, chemical modification, and substrate specificity studies were used to compare possible mechanistic similarities of 3-hydroxyisobutyrate dehydrogenase with 6-phosphogluconate dehydrogenase. The data suggest that 3-hydroxyisobutyrate and 6-phosphogluconate dehydrogenases may comprise, in part, a previously unrecognized family of 3-hydroxyacid dehydrogenases.
Hawes
J W
JW
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202-5122, USA.
Harper
E T
ET
Crabb
D W
DW
Harris
R A
RA
D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019143:Evolution, Molecular; D007700:Kinetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010734:Phosphogluconate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism; D011549:Pseudomonas / Q000201:enzymology; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D011732:Pyridoxal Phosphate; D000429:Alcohol Oxidoreductases; C021398:3-hydroxyisobutyrate dehydrogenase; D010734:Phosphogluconate Dehydrogenase