Date of Award

1994

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Richard D. Gandour

Abstract

Carnitine acetyltransferase (CAT) catalyzes the reversible transfer of short chain (less than six carbons in length) acyl groups between carnitine and coenzyme A (CoA). This reaction likely modulates the reserves of free CoA and acetyl-CoA in each organelle and membrane in ways specific to the local demands. To probe the structures of the molecular interactions between carnitine and the active site in CAT, we have designed and synthesized conformationally constrained reaction-intermediate analogues, which not only inhibit enzymatic activity, but also help reveal the topography of the active site. The syntheses of (2R,6R)-, (2S,6S)-, (2R,6S)-, and (2S,6R)-6-carboxylatomethyl-2-hydroxymethyl-2,4,4-trimethylmorpholinium are described. The single-crystal X-ray structures of these compounds are presented. These four stereoisomers are tested as specific inhibitors of CAT. The results confirm the hypothesis that there is two-point recognition by CAT for carnitine and acetyl-CoA is the third locus for chiral recognition. The results also strongly support the proposed mechanism for acetyl transfer between carnitine and CoA. The syntheses of methyl (2S,6S;2R,6R)- and (2S,6R;2R,6S)-2- (6-(2-cyanoethyl)-4,6-dimethylmorpholinyl) acetate and the resolution of 5-(N,N-dimethylamino)-4-hydroxy-4-methylpentanenitrile are also described.

Pages

130

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