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Enzyme catalysis of nucleophilic attack of anions by anions

酶催化阴离子亲核攻击阴离子

基本信息

批准号：
BB/M021637/1
负责人：
Jon Waltho
金额：
$ 45.53万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM021637%2F1
关键词：
Enzyme catalysis nucleophilic attack anions

项目摘要

The present application aims to get to the heart of fundamental questions that are critical to developing our understanding of how enzymes work. Enzymes, which are normally proteins, control the rate at which almost all chemistry occurs in living systems. Understanding enzyme activity is a high priority - it is at the core of therapeutic intervention, industrial biotechnology, and synthetic biology. The controlled manipulation of enzyme activity is one of the key elements targeted in each of these areas of research. Enzyme activity has been studied for many decades and many paradigms have evolved but, very recently, tools have been developed that allow the testing of those paradigms with unprecedented levels of detail. We are now able to observe the structure, electronics and dynamics within enzymes at the level of individual atoms. A proper understanding of all of these elements and their interplay is crucial to manipulating enzyme activity, and with observation powers at this level of detail, many of traditional paradigms of enzymology are not surviving rigorous testing. In this study we will examine how enzymes handle chemistry between two entities with the same charge, how the enzyme is triggered to open and close, and how it avoids getting stuck in deep thermodynamic wells when dealing with high-energy reactions. These issues are fundamental to the activity of many enzymes and are not well understood. To achieve the study we will investigate the behaviour of an enzyme that moves phosphate groups between a carboxylate group and a phosphate group, and between two phosphate groups. Enzymes that move phosphate groups lie at the heart of every system in living organisms - in the storage, maintenance and expression of genetic information, in metabolism, communication, cell architecture, differentiation, and homeostasis. We will develop new models based on the behaviour an archetypal enzyme that delivers very high quality measurements, which can then be translated to other enzymes that are common targets in therapeutic, industrial biotechnology and synthetic biology programmes.

本申请旨在触及对发展我们对酶如何工作的理解至关重要的基本问题的核心。酶，通常是蛋白质，控制着生命系统中几乎所有化学反应的速率。了解酶的活性是一个高度优先事项-它是治疗干预，工业生物技术和合成生物学的核心。酶活性的受控操纵是这些研究领域中每个领域的关键目标之一。酶的活性已经研究了几十年，许多范式已经发展，但最近，已经开发了工具，允许测试这些范式与前所未有的细节水平。我们现在能够在单个原子的水平上观察酶的结构，电子和动力学。正确理解所有这些元素及其相互作用对于操纵酶活性至关重要，并且在这种细节水平上的观察能力，许多传统的酶学范式无法经受严格的测试。在这项研究中，我们将研究酶如何处理具有相同电荷的两个实体之间的化学反应，如何触发酶打开和关闭，以及如何避免在处理高能反应时陷入深层热力学威尔斯。这些问题对于许多酶的活性是基本的，并且还没有很好地理解。为了实现这项研究，我们将研究一种酶的行为，这种酶在羧酸基团和磷酸基团之间以及两个磷酸基团之间移动磷酸基团。移动磷酸基团的酶位于生物体中每个系统的核心-在遗传信息的存储，维护和表达，新陈代谢，通信，细胞结构，分化和稳态中。我们将开发基于行为的新模型，这种原型酶可以提供非常高质量的测量，然后可以将其转化为治疗，工业生物技术和合成生物学计划中的常见目标的其他酶。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regional conformational flexibility couples substrate specificity and scissile phosphate diester selectivity in human flap endonuclease 1.

DOI：
10.1093/nar/gky293
发表时间：
2018-06-20
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Bennet IA;Finger LD;Baxter NJ;Ambrose B;Hounslow AM;Thompson MJ;Exell JC;Shahari NNBM;Craggs TD;Waltho JP;Grasby JA
通讯作者：
Grasby JA

How to name atoms in phosphates, polyphosphates, their derivatives and mimics, and transition state analogues for enzyme-catalysed phosphoryl transfer reactions (IUPAC Recommendations 2016)