糖氧甲基转移酶MycE催化麦新米星VI甲基转移机理的理论研究

项目名称： 糖氧甲基转移酶MycE催化麦新米星VI甲基转移机理的理论研究

项目编号： No.21503026

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 数理科学和化学

项目作者： 张成华

作者单位： 川北医学院

项目金额： 21万元

中文摘要： 取代糖的氧甲基化是大环内酯类抗生素和其它天然产物生物合成途径的常见修饰，且由糖O-甲基转移酶催化。麦新米星（mycinamicins）是一种大环内酯类抗生素，它的第一步甲基化由麦新米星VI 2’’-O-甲基转移酶（MycE）催化完成。本项目拟利用量子化学和混合量子力学/分子力学(QM/MM)方法，构建合理的麦新米星VI与MycE的复合物模型，详细研究底物的结合模式、部份酶残基及整个酶环境下麦新米星VI甲基化过程，探索糖氧甲基转移酶MycE催化麦星米星VI甲基转移的机理。本项目拟解决两大难题：一是确定酶催化甲基化过程的反应复合物、过渡态结构以及质子转移和甲基转移是协同还是分步过程，获取完整的甲基化机理；二是阐明反应中心氨基酸残基和金属离子对催化机理的影响。本项目的研究将为设计并修改麦新米星及其它类似抗生素的现有生物合成途径、设计仿生催化剂和研究糖O-甲基转移酶家族的催化反应机制提供理论基础。

中文关键词： 糖氧甲基转移酶；麦新米星VI；酶催化；甲基转移；计算模拟

英文摘要： O-linked methylation of sugar substituents is a common modification in the biosynthesis of macrolide antibiotics and other natural products, and is catalyzed by sugar O-methyltransferases. Mycinamicins, a potent macrolide antibiotics, and the first methylation is catalyzed by mycinamicin VI 2’’-O-methyltransferase (MycE). This project intends to employ the quantum chemistry and the hybrid quantum mechanical/molecular mechanical (QM/MM) approach to study the methyl transfer mechanism of mycinamicin VI catalyzed by sugar O-methyltransferase MycE, by building a reasonable model of mycinamicin VI in complex with MycE, which will be investigated in detail to illustrate the substrate binding, the methylation reaction mechanism under part of the enzyme residues and under the whole enzyme environment. There are two major tasks in this project. (i) To determine the reactant complex, transition state structure, determine the proton transfer and methyl transfer proceed through a concerted mechanism or stepwise in the enzymatic methylation, and obtain a complete methylation mechanism; (ii) To clarify interplay of amino acid residues and metal ions in the catalytic mechanism. This project may provide theoretical basis for designing and modifying the existing antibiotics biosynthetic pathways, designing biomimetic catalysts and studying the reaction mechanism catalyzed by the sugar O-methyltransferase family.

英文关键词： sugar O-methyltransferases;mycinamicin VI;enzymatic catalysis;methyl transfer;computer simulation