Mammalian branched-chain acyl-CoA dehydrogenases: Molecular cloning and characterization of recombinant enzymes

The acyl-CoA dehydrogenases (ACDs) are a family of related enzymes that catalyze the α, β-dehydrogenation of acyl-CoA esters, transferring electrons to electron-transferring flavoprotein. Deficiencies of these enzymes are important causes of human disease. Biochemical and immunological studies have identified at least seven distinct members of this enzyme family, each with narrow substrate specificity. Two ACDs are active in the metabolism of branched-chain amino acids. Isovaleryl-CoA dehydrogenase (IVD) and short/branched-chain acyl-CoA dehydrogenase catalyze the third step in leucine and isoleucine/valine metabolism, respectively. Complementary DNAs for each of the rat and human ACDs have been cloned by a variety of techniques. DNA sequencing studies show that the amino acid sequences of the various enzymes share 30–35% identical residues, indicating that the enzymes are encoded by separate but related genes. Interspecies identities between the same ACDs approach 90%. Thus, it is likely that these genes have evolved from a common ancestral gene and have attained their distinct substrate specificities through evolutionary divergence. The three-dimensional structures of porcine medium-chain acyl-CoA dehydrogenases, Megasphaera esdenii butyryl-CoA dehydrogenase, rat short-chain acyl-CoA dehydrogenases, and human IVD have also been reported to be similar.