R-(-)-carnitine (L-carnitine) is a substrate for at least three carnitine acyltransferases, which differ in chain length specificity for the acyl group. The short chain enzyme, carnitine acetyltransferase (CAT), is important for maintaining the acetyl-CoA/CoASH ration, while the long chain enzyme, carnitine palmitoyltransferase 1 (CPT-1), is required to activate long chain fatty acids for entry into mitochondria. Both exogenous carnitine and inhibitors of CPT-1 have been shown to have beneficial effects in heart in that they protect the ischemic myocardium. Thus a better understanding of these enzymes may offer a basis for the design of important new therapeutic agents useful in the treatment of ischemic heart disease. Carnitine is a conformationally flexible molecule. While a single low energy conformer about C3-C4 is highly favored, several low energy conformers about C2-C3 are possible. We are interested in determining the active conformations for carnitine and acylcarnitines about C2-C3 upon binding to CAT and CPT-1. In particular, it is of interest to determine if these enzymes bind to different low energy conformations of carnitine, which would offer the possibility of selectively for new therapeutic agents. Toward this end, we will synthesize, separate the diastereomers, resolve into enantiomers, and assign the absolute configurations for conformationally rigid carnitine analogues 1-12. All analogues contain the correct information about C3-C4, and all low energy conformations about C2-C3 are represented. The appropriate analogues will be evaluated as alternate substrates and inhibitors of purified pigeon breast CAT and bovine heart CPT-1 (intact mitochondria) for both the forward and reverse reactions.
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