Acyl and phosphoryl group transfer reactions are essential parts of the biochemistry of living systems. Little is known about the influences of leaving group and nucleophile, and the effect of catalytic groups, on the mechanisms and transition states of these reactions. This work will address these questions using a variety of isotope effect studies. Preliminary work supports a change from a stepwise mechanism with a tetrahedral intermediate to a concerted mechanism for acyl transfer reactions of esters with good leaving groups. The specific goals of the work in this proposal are to: 1. Obtain detailed descriptions of the transition states for acyl and phosphoryl transfer reactions in solution and in enzymatic reactions. Comparisons of these will shed light on the effect of the enzymatic catalytic groups on transition state structure. 2. Analyze differences in mechanism and in transition state structure that arise from changes in the leaving group and in the nucleophile (changes in basicity or nucleophilicity, and in identity of the attaching atom, for example, oxygen versus sulfur nucleophiles) in solution and enzymatic reactions. 3. Delineate the boundaries of the limiting concerted vs. stepwise mechanisms as determined by properties of nucleophile and/or leaving group in the solution and in enzymatic reactions. 4. Determine whether activated substrates undergo enzymatic group transfer reactions by the same mechanisms as unactivated ones, or if the mechanisms differ, as they do in solution.
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