Mechanism and inhibition of organic and enzymatic isomerizations

有机和酶异构化的机理和抑制

• 批准号: 2317422
• 负责人: Andrew Murkin
• 金额: $ 54.32万
• 依托单位: SUNY at Buffalo
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2317422&HistoricalAwards=false
• 关键词: Mechanism; inhibition; organic; enzymatic; isomerizations

With the support of the Chemistry of Life Processes program of the Division of Chemistry, Andrew Murkin of the University at Buffalo, the State University of New York, is studying the mechanisms of isomerization in organic and enzymatic reactions. Isomerization—the conversion of one compound into another without a change in molecular formula—is critical to the synthesis of many chemicals and biomolecules. Three examples of a specific isomerization reaction will be investigated, one using organic compounds in the presence of a catalyst and the other two using enzymes from organisms that cause severe infections such as tuberculosis. Learning how these reactions proceed may lead to the development of improved catalysts and of pharmaceuticals that act by inhibiting enzymes associated with various diseases. Educational development will be provided to undergraduate and graduate students of diverse backgrounds, and local teachers will be trained to develop hands-on lessons that introduce enzymes to K–12 students.This project seeks to determine the mechanisms of Lewis acid- and enzyme-catalyzed rearrangement of alpha-ketol substrates using substituent effects and kinetic isotope effects (KIEs). The BF3-catalyzed rearrangement of dibenzylglycolaldehyde derivatives will be investigated first, and estimates the transition state structure will be established by quantum mechanical calculations that utilize the experimental results on the nature of the rate-determining step. This structure will serve as a model for comparison with the transition states of two enzyme-catalyzed reactions that also involve rearrangement of alpha-ketols. Of the two enzymes, one is expected to utilize a mechanism analogous to the Lewis acid-catalyzed reaction and should be directly comparable. Most evidence to date on the second enzyme, however, favors an alternative mechanism not possible for the first enzyme. This project therefore aims to clarify this uncertainty, the outcome of which may guide the design of inhibitors tailored to these enzymes. In the longer term, these studies have the potential to guide the development of transition state analogue inhibitors for isomerase enzymes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系生命过程化学项目的支持下，布法罗大学、纽约州立大学的安德鲁·默金正在研究有机反应和酶反应中异构化的机理。异构化--一种化合物转化为另一种化合物而不改变分子式--对许多化学品和生物分子的合成至关重要。将研究三个具体异构化反应的例子，一个是在催化剂存在下使用有机化合物，另两个是使用来自引起严重感染（如结核病）的生物体的酶。了解这些反应是如何进行的可能会导致改进催化剂和药物的开发，这些药物通过抑制与各种疾病相关的酶来发挥作用。将为不同背景的本科生和研究生提供教育发展，并培训当地教师，以开发实践课程，向K-12学生介绍酶。本项目旨在确定刘易斯酸和酶催化的α-酮醇底物重排的机理，使用取代基效应和动力学同位素效应（KIE）。BF 3催化重排的二苄基乙醇醛衍生物将首先进行研究，并估计过渡态结构将建立量子力学计算，利用实验结果的性质的速率决定步骤。这种结构将作为一个模型，与过渡态的两个酶催化的反应，也涉及重排的α-酮醇的比较。在这两种酶中，预期一种酶利用类似于刘易斯酸催化反应的机制，并且应该是直接可比的。然而，迄今为止关于第二种酶的大多数证据都支持第一种酶不可能的替代机制。因此，该项目旨在澄清这种不确定性，其结果可能会指导针对这些酶的抑制剂的设计。 从长远来看，这些研究有可能指导异构酶的过渡态类似物抑制剂的开发。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。