Role of binding determinants in enzyme catalysis

结合决定簇在酶催化中的作用

• 批准号: 194261-2008
• 负责人: Bearne, Stephen
• 金额: $ 3.76万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=546089
• 关键词: Role; binding; determinants; enzyme; catalysis

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.

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如何实现这种反应速率的加速。 具体来说，我正在开发一个详细的了解酶和底物分子之间发生的相互作用，他们的作用。这些知识是必不可少的了解酶如何工作，工程合成酶催化剂，并设计潜在的酶抑制剂（药物）。 为此，我正在研究扁桃酸消旋酶。 这种酶催化D-和L-扁桃酸的相互转化，并在某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键裂解）。 在以前工作的基础上，我将确定底物结合如何改变酶催化中心氨基酸侧链的酸性。 我已经发现，扁桃酸消旋酶被抑制的底物产物类似物，我将进一步发展这一发现，通过评估是否其他消旋酶也被抑制的底物产物类似物，这是否是一个通用的策略，为开发相关酶的抑制剂，药物设计的目标。 我还在进行实验，以解决一个基本问题，即在进化过程中，酶如何降低反应的能量障碍以实现催化作用。 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。 目前的建议解决酶学和进化的基本问题，其结果应提供洞察抑制剂设计的一般策略，这将是有用的知识，以帮助药物开发。