Molecular Basis Disorders of Branched Chain Amino Acids

Tanaka, Kay

Abstract

It is our overall objective to elucidate the biochemical and genetic basis underlying disorders of organic acid metabolism. The study of various acyl dehydrogenases and disorders due to the deficient activity of these enzymes (human acyl CoA dehydrogenase mutants) such as isovaleric acidemia, glutaric aciduria type II, and ethylmalonic-adipic aciduria are the major objectives of the present proposal. A number of new questions concerning the existence of some hitherto unknown enzymes and electron carrier proteins, substrate specificity, reaction mechanisms, and molecular homology and heterogeneity of varius acyl CoA dehydrogenases have been raised from studies of the human acyl CoA dehydrogenase mutants. With these proposed studies, we hope to gain new insight into the molecular structure and function on the various acyl CoA dehydrogenases and to obtain information for a clearer understanding of the biochemical basis of the human acyl CoA dehydrogenase mutants. Individual projects are as follows: a. Purification and characterization of various acyl CoA dehydrogenases from animal and human liver. b. Studies on the mechanisms of dehydrogenation and electron transport from acyl CoAs. c. Studies of the biochemical and genetic mechanisms of human acyl CoA dehydrogenase mutants.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Type: Method to Extend Research in Time (MERIT) Award (R37)
• Project #: 5R37DK017453-17
• Application #: 3483207
• Study Section: Biochemistry Study Section (BIO)
• Project Start: 1977-03-01
• Project End: 1992-02-29
• Budget Start: 1989-03-01
• Budget End: 1990-02-28
• Support Year: 17
• Fiscal Year: 1989

Institution

• Name: Yale University
• Type: Schools of Medicine
• DUNS #: 082359691
• City: New Haven
• State: CT
• Country: United States
• Zip Code: 06520

Publications

Parimoo, B; Tanaka, K (1993) Structural organization of the human isovaleryl-CoA dehydrogenase gene. Genomics 15:582-90

Vockley, J; Nagao, M; Parimoo, B et al. (1992) The variant human isovaleryl-CoA dehydrogenase gene responsible for type II isovaleric acidemia determines an RNA splicing error, leading to the deletion of the entire second coding exon and the production of a truncated precursor protein that interacts p J Biol Chem 267:2494-501

Vockley, J; Parimoo, B; Nagao, M et al. (1992) Identification of the molecular defects responsible for the various genotypes of isovaleric acidemia. Prog Clin Biol Res 375:533-40

Nagao, M; Tanaka, K (1992) FAD-dependent regulation of transcription, translation, post-translational processing, and post-processing stability of various mitochondrial acyl-CoA dehydrogenases and of electron transfer flavoprotein and the site of holoenzyme formation. J Biol Chem 267:17925-32

Vockley, J; Parimoo, B; Tanaka, K (1991) Molecular characterization of four different classes of mutations in the isovaleryl-CoA dehydrogenase gene responsible for isovaleric acidemia. Am J Hum Genet 49:147-57

Indo, Y; Glassberg, R; Yokota, I et al. (1991) Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable matur Am J Hum Genet 49:575-80

Rinaldo, P; Welch, R D; Previs, S F et al. (1991) Ethylmalonic/adipic aciduria: effects of oral medium-chain triglycerides, carnitine, and glycine on urinary excretion of organic acids, acylcarnitines, and acylglycines. Pediatr Res 30:216-21

Ito, M; Ikeda, Y; Arnez, J G et al. (1990) The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. Biochim Biophys Acta 1034:213-8

Rinaldo, P; O'Shea, J J; Welch, R D et al. (1990) The enzymatic basis for the dehydrogenation of 3-phenylpropionic acid: in vitro reaction of 3-phenylpropionyl-CoA with various acyl-CoA dehydrogenases. Pediatr Res 27:501-7

Ikeda, Y; Tanaka, K (1990) Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA. Biochim Biophys Acta 1038:216-21