Mechanisms of Enzymatic Catalysis

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The proposed research involves the catalytic mechanism of bovine liver glutamate dehydrogenase. The timing of bond-making and bond- breaking processes as well as proton transfers will be determined for both the forward and reverse reactions catalyzed by the enzyme. The catalytic reaction coordinate will be correlated with enzyme conformation changes which are known to alter solvent access to the active site. Mechanistic results will be correlated with available protein three dimensional structural information to arrive at a unified description of the catalytic process as a function of time. %%% Enzyme mechanism studies characterize the step by step processes involving the enzyme, solvent, and substrate(s) which occur during catalysis. Developing a self-consistent picture of an enzyme mechanism is difficult and laborious, requiring application of structural, chemical, as well as kinetic information. It is the most difficult and potentially most rewarding study that can be undertaken with enzymes, which are in their very essence active and time-dependent entities. Knowledge of mechanism allows manipulation of the enzyme's catalytic machinery to carry out chemistry and permits design of inhibitors of the enzyme which often turn out to be potent drugs.