Short chain L-3-hydroxyacyl CoA dehydrogenase (SCHAD) is a mitochondrial enzyme involved in the metabolism of fatty acids. It catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl CoA to a keto group, concomitant with the reduction of NAD+ to NADH. Deficiencies in this enzyme result in various disease states, including hypertrophic cardiomyopathy, skeletal myopathy, hypoketotic hypoglycemia, and liver dysfunction. The proposed research utilizes a multi-faceted approach to understanding the structure-function relationships present in human SCHAD. SCHAD will be purified to homogeneity from an appropriate expression system and its kinetic properties characterized. Crystals of human SCHAD suitable for x-ray diffraction studies will then be prepared in order to resolve the three-dimensional structure of the apoenzyme, the NAD+-complexed enzyme, and the acyl-CoA-complexed enzyme. Site directed mutagenesis and rational inhibitor design studies will be initiated to confirm or further develop our understanding of the enzyme mechanism. Characterization of SCHAD would provide information about the method of action of analogous proteins, such as long chain (LCHAD) and peroxisomal L-3-hydroxyacyl CoA dehydrogenases. These studies would help explain the mutations which result in SCHAD and LCHAD deficiencies, and provide a greater understanding of the disease states associated with these deficiencies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK009759-02
Application #
6054677
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Hyde, James F
Project Start
2000-01-01
Project End
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455