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 Arthritis, Diabetes, Digestive and Kidney Diseases (NIADDK)
Type
Research Project (R01)
Project #
5R01AM017453-13
Application #
3151064
Study Section
(ABC)
Project Start
1977-03-01
Project End
1987-02-28
Budget Start
1985-03-01
Budget End
1986-02-28
Support Year
13
Fiscal Year
1985
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

  Publications

Finocchiaro, G; Ito, M; Tanaka, K (1988) Purification and properties of short-chain acyl-CoA, medium-chain acyl-CoA, and isovaleryl-CoA dehydrogenases from human liver. Adv Neurol 48:221-30
Ikeda, Y; Tanaka, K (1987) Immunoprecipitation and electrophoretic analysis of four human acyl-CoA dehydrogenases and electron transfer flavoprotein using antibodies raised against the corresponding rat enzymes. Biochem Med Metab Biol 37:329-34
Ikeda, Y; Keese, S M; Fenton, W A et al. (1987) Biosynthesis of four rat liver mitochondrial acyl-CoA dehydrogenases: in vitro synthesis, import into mitochondria, and processing of their precursors in a cell-free system and in cultured cells. Arch Biochem Biophys 252:662-74
Finocchiaro, G; Ito, M; Tanaka, K (1987) Purification and properties of short chain acyl-CoA, medium chain acyl-CoA, and isovaleryl-CoA dehydrogenases from human liver. J Biol Chem 262:7982-9
Ikeda, Y; Keese, S M; Tanaka, K (1986) Biosynthesis of electron transfer flavoprotein in a cell-free system and in cultured human fibroblasts. Defect in the alpha subunit synthesis is a primary lesion in glutaric aciduria type II. J Clin Invest 78:997-1002
Ikeda, Y; Hale, D E; Keese, S M et al. (1986) Biosynthesis of variant medium chain acyl-CoA dehydrogenase in cultured fibroblasts from patients with medium chain acyl-CoA dehydrogenase deficiency. Pediatr Res 20:843-7
Hyman, D B; Tanaka, K (1986) Isovaleryl-CoA dehydrogenase activity in isovaleric acidemia fibroblasts using an improved tritium release assay. Pediatr Res 20:59-61
Matsubara, Y; Kraus, J P; Yang-Feng, T L et al. (1986) Molecular cloning of cDNAs encoding rat and human medium-chain acyl-CoA dehydrogenase and assignment of the gene to human chromosome 1. Proc Natl Acad Sci U S A 83:6543-7
Okamura-Ikeda, K; Ikeda, Y; Tanaka, K (1985) An essential cysteine residue located in the vicinity of the FAD-binding site in short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases from rat liver mitochondria. J Biol Chem 260:1338-45
Ikeda, Y; Keese, S M; Tanaka, K (1985) Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts. Proc Natl Acad Sci U S A 82:7081-5

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