The mitochondrial carnitine palmitoyltransferase (CPT) enzyme system (composed of CPT I, CPT II and a translocase component) plays a pivotal role in the regulation of fatty acid metabolism in mammalian tissues. Recently it has received increasing attention as a potential site for pharmacological intervention in hyperglycemic states, and is now recognized as a locus of human mutations, some with serious consequences. For a number of years we have sought to unravel the complexities of the CPT isozymes, and during the past grant period have uncovered some novel and unexpected features surrounding their biochemical and functional properties. Using cloning techniques we have now reached the threshold of an exciting era that promises to shed new light on the subject at a molecular level (e.g., for the first time we have obtained the complete amino acid sequence of a CPT enzyme). Continuing in this vein our overall objectives are to elucidate the actual structures of the rat and human CPT proteins, their regulatory properties, the organization of their genes, and the nature of inherited defects in enzyme activity. Four main questions will be posed: (1) How do the primary amino acid sequences of CPT I and CPT II compare in different tissues? (2) How do CPT I and CPT II interact with their respective membranes, substrates and inhibitors? (3) How do the rat genes for CPT I and CPT II compare in number and structure? (4) How do the human CPT genes and gene products relate to their rat counterparts, and what is the genetic basis for the inherited CPT deficiency syndromes? Answers to these questions would transform current understanding of mitochondrial fatty acid transport from the realm of vague, operational definitions to one of concrete, biochemical principles. In addition, the information gained could lead to diagnostic, and possibly therapeutic, advances in the arena of disease states characterized by excessive or inadequate rates of fatty acid oxidation.

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 #
5R37DK018573-32
Application #
3483262
Study Section
Metabolism Study Section (MET)
Project Start
1975-06-01
Project End
1995-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
32
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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