Role of binding determinants in enzyme catalysis

酶是加速（催化）生物反应的蛋白质。我的研究重点是详细了解酶是如何实现这种加速反应速率的。具体来说，我正在对酶和它们作用的底物分子之间发生的相互作用有一个详细的了解。这些知识对于理解酶如何工作、设计合成酶催化剂和设计潜在的酶抑制剂（药物）至关重要。为此，我正在研究扁桃形外消旋酶。该酶催化D-和l -扁桃酸的相互转化，并在一些土壤细菌的代谢中起作用。该酶作为理解酶如何催化不利反应（例如，C-H键切割）的范例。在先前工作的基础上，我将确定底物结合如何改变酶催化中心氨基酸侧链的酸度。我发现扁豆酸外消旋酶被底物产物类似物抑制，我将通过评估其他外消旋酶是否也被底物产物类似物抑制，以及这是否是开发相关酶抑制剂的一般策略来进一步发展这一发现，这些酶抑制剂是药物设计的目标。我也在进行实验，以解决一个基本问题，即在进化过程中，酶是如何降低反应的能垒以达到催化作用的。最后，我正在研究在极端温度下发挥作用的酶。这些所谓的极端酶有许多实际应用。目前的建议解决了酶学和进化中的基本问题，结果应该为抑制剂设计的一般策略提供见解，这将是帮助药物开发的有用知识。

Enzymes are proteins that accelerate (catalyze) biological reactions. My research focuses on developing a detailed understanding of how enzymes accomplish this acceleration of reactions rates. Specifically, I am developing a detailed understanding of the interactions that occur between enzymes and the substrate molecules that they act on. This knowledge is essential to understanding how enzymes work, to engineer synthetic enzyme catalysts, and to design potential inhibitors of enzymes (drugs). For this purpose, I am studying mandelate racemase. This enzyme catalyzes the interconversion of D- and L-mandelic acid and plays a role in the metabolism of some soil bacteria. The enzyme serves as a paradigm for understanding how enzymes catalyze unfavorable reactions (e.g., C-H bond cleavage). Building on previous work, I will determine how substrate binding changes the acidity of amino acid side chains that reside in the enzyme's catalytic center. I have discovered that mandelate racemase is inhibited by substrate-product analogues and I will develop this finding further by assessing whether other racemases are also inhibited by substrate-product analogues and whether this is a general strategy for the development of inhibitors of related enzymes that are targets for drug design. I am also conducting experiments to address the fundamental question of how, over the course of evolution, enzymes lower the energy barrier of a reaction to achieve catalysis. Finally, I am studying enzymes that function at extremes of temperature. These so-called extremozymes have many practical applications. The present proposal addresses fundamental issues in enzymology and evolution, and the results should provide insights into general strategies for inhibitor design which will be useful knowledge for aiding drug development.