Enzyme Structure-Function Relationships

提出了两种方法来研究 配体结构-功能关系 结合亲和力和催化机制的两个不同的 T4噬菌体二氢叶酸还原酶（T4 DHFR） 和柠檬酸合酶（CS）。 第一个将是 结构的晶体学分析 这些酶的结构比较， 配体亲和力和催化活性，以及进一步的 与已知的远亲或 酶的突变形式。 第二种方法将 涉及对静电场作用的研究 在这些酶中。 二氢叶酸还原酶催化一个环状的 DNA合成的关键途径。 特别是 对合成叶酸抑制作用高度敏感 化合物，表现出高物种选择性。 这些化合物 对于控制快速的 分裂细胞 柠檬酸合酶催化缩合 草酰乙酸和乙酰辅酶A形成柠檬酸， 辅酶A 它是少数几种能够直接 形成碳-碳键。 它呈现出前所未有的 有机会研究一种不寻常的机制， 包括连续的构象变化和静电 底物的不稳定化。*//

Two approaches are proposed to investigate the structure-function relationships responsible for ligand binding affinities and catalytic mechanisms of two different enzymes, T4 bacteriophage dihydrofolate reductase (T4 DHFR) and citrate synthase (CS). The first will be a crystallographic analysis of the structures of the enzymes, a comparison of these structures in terms of ligand affinities and catalytic activity and a further comparison with known structures of distantly related or mutant forms of the enzymes. The second approach will involve an investigation of the role of electrostatic fields in these enzymes. Dihydrofolate reductase catalyzes a reaction in a cyclic pathway essential to DNA synthesis. In particular, it is highly susceptible to inhibition by synthetic folate compounds, showing high species selectivity. These compounds are of considerable interest for the control of rapidly dividing cells. Citrate synthase catalyzes the condensation of oxaloacetate and acetylCoenzyme A to form citrate and Coenzyme A. It is one of a few enzymes capable of directly forming a carbon-carbon bond. It presents an unprecedented opportunity to examine an unusual mechanism which probably involves sequential conformational changes and electrostatic destabilization of substrate.***//