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 #
5R37DK017453-16
Application #
3483206
Study Section
Biochemistry Study Section (BIO)
Project Start
1977-03-01
Project End
1992-02-29
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
16
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

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

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