title: Molecular basis of isovaleric acidemia and medium-chain acyl-CoA dehydrogenase deficiency.
abstract: Our early study of isovaleric acidemia (IVA) indicated that isovaleryl-CoA is dehydrogenated by an enzyme that is specific for isovaleryl-CoA. We subsequently identified and purified isovaleryl-CoA dehydrogenase (IVD) and 2-methyl-branched chain acyl-CoA dehydrogenase, which were previously unknown. We also purified and characterized three previously known acyl-CoA dehydrogenases. Five acyl-CoA dehydrogenases share similar molecular features and reaction mechanisms, indicating a close evolutionary relationship. Using the tritium release assay and [35S]methionine labeling/immunoprecipitation, we showed that IVA is due to a mutation of IVD. We also demonstrated that there are at least 5 distinct forms of mutant IVD, indicating an extensive molecular heterogeneity. Furthermore, we cloned cDNAs encoding IVD and medium-chain acyl-CoA dehydrogenases. The comparison of their complete primary sequences revealed a high degree of homology, indicating that these enzymes belong to a gene family, the acyl-CoA dehydrogenase family.
authors.affiliation: Department of Human Genetics, Yale University School of Medicine, New Haven, Conn.
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Matsubara
authors.forename: D B
authors.initials: DB
authors.lastname: Hyman
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000172:deficiency* / Q000235:genetics* / Q000302:isolation & purification; D000595:Amino Acid Sequence; D001483:Base Sequence; D004270:DNA, Circular / Q000235:genetics*; D045782:Hemiterpenes; D006801:Humans; D050769:Isovaleryl-CoA Dehydrogenase; D008661:Metabolism, Inborn Errors / Q000097:blood* / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010421:Pentanoic Acids / Q000097:blood*; D014176:Protein Biosynthesis; D012689:Sequence Homology, Nucleic Acid; D014631:Valerates / Q000097:blood*
chemical_list: D004270:DNA, Circular; D045782:Hemiterpenes; D010421:Pentanoic Acids; D014631:Valerates; C008216:isovaleric acid; D010088:Oxidoreductases; D044944:Acyl-CoA Dehydrogenases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050769:Isovaleryl-CoA Dehydrogenase