The acyl-CoA dehydrogenases (ACDs) are a family of evolutionarily related enzymes involved in the first step of the B-oxidation of fatty acids and in the intermediate metabolism of leucine, isoleucine and valine. Deficiencies of these enzymes are important causes of inherited defects of metabolism in humans. The long-range objective of this project has been to investigate important structure/function relationships in the ACD gene family. Our general hypothesis is that this information will afford a better understanding of genotype/phenotype correlations in patients with deficiencies of these enzymes. In previous funding periods, we have made significant strides in characterizing the structure, enzymatic properties, and biogenesis of isovaleryl-CoA dehydrogenase (IVD), as well as identifying numerous IVD mutations in patients with isovaleric acidemia.
Specific aims for this renewal application include Aim 1: characterization of WD catalytic function;
Aim 2 : determination of amino acid residues and motifs important for stabilization of IVD homotetrainers;
and Aim 3 : elucidation of the mechanism of interaction of ACDs with electron transferring flavoprotein, the physiologic electron acceptor for these enzyme. Site specific mutagenesis directed by structural analysis and molecular modeling will be used to create mutant enzymes, and new biophysical techniques will be developed which will facilitate study of these properties. This work will lead to a more complete understanding of the ACD gene family, and ultimately, to an improved ability to diagnose and treat patients with deficiencies of these enzymes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK045482-08
Application #
6326230
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Mckeon, Catherine T
Project Start
1993-08-01
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
8
Fiscal Year
2001
Total Cost
$254,813
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Tein, Ingrid; Elpeleg, Orly; Ben-Zeev, Bruria et al. (2008) Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin. Mol Genet Metab 93:179-89
He, M; Rutledge, S L; Kelly, D R et al. (2007) A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Am J Hum Genet 81:87-103
Lee, Yong-Wha; Lee, Dong Hwan; Vockley, Jerry et al. (2007) Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with isovaleric acidemia. Mol Genet Metab 92:71-7
Goetzman, Eric S; Wang, Yudong; He, Miao et al. (2007) Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab 91:138-47
Vockley, Jerry; Ensenauer, Regina (2006) Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet 142C:95-103
Conlon, Thomas J; Walter, Glenn; Owen, Renius et al. (2006) Systemic correction of a fatty acid oxidation defect by intramuscular injection of a recombinant adeno-associated virus vector. Hum Gene Ther 17:71-80
Merritt 2nd, J Lawrence; Matern, Dietrich; Vockley, Jerry et al. (2006) In vitro characterization and in vivo expression of human very-long chain acyl-CoA dehydrogenase. Mol Genet Metab 88:351-8
Goetzman, Eric S; He, Miao; Nguyen, Tien V et al. (2006) Functional analysis of acyl-CoA dehydrogenase catalytic residue mutants using surface plasmon resonance and circular dichroism. Mol Genet Metab 87:233-42
Goetzman, Eric S; Mohsen, Al-Walid A; Prasad, Kavita et al. (2005) Convergent evolution of a 2-methylbutyryl-CoA dehydrogenase from isovaleryl-CoA dehydrogenase in Solanum tuberosum. J Biol Chem 280:4873-9
Schowalter, David B; Matern, Dietrich; Vockley, Jerry (2005) In vitro correction of medium chain acyl CoA dehydrogenase deficiency with a recombinant adenoviral vector. Mol Genet Metab 85:88-95

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