Mechanisms of Enzymatic Catalysis

本研究涉及牛肝谷氨酸脱氢酶的催化机理。对于酶催化的正向和反向反应，将确定成键和断键过程以及质子转移的时间。催化反应坐标将与酶的构象变化相关联，这些变化已知会改变溶剂对活性部位的访问。机理结果将与可用的蛋白质三维结构信息相关联，以得到作为时间函数的催化过程的统一描述。%酶机理研究描述了催化过程中涉及酶、溶剂和底物(S)的逐步过程。开发一张自洽的酶机制图是困难和费力的，需要应用结构、化学和动力学信息。这是可以用酶进行的最困难和潜在最有回报的研究，酶本质上是活跃的和依赖时间的实体。对机理的了解允许操纵酶的催化机制来进行化学操作，并允许设计酶的抑制剂，这些抑制剂往往被证明是有效的药物。

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.