Structural and mechanistic similarities of 6‐phosphogluconate and 3‐hydroxyisobutyrate dehydrogenases reveal a new enzyme family, the 3‐hydroxyacid dehydrogenases

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Abstract
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.