人工辅因子的理性设计、作用机制及应用研究

Our previous study indicated that the modification of molecular structure of natural cofactors can effectively influence their catalytic performance, thus to achieve the purpose of regulation of biocatalysis process, part of the research work showed good industrial application prospects. However, the recognition mechanism between artificial cofactors and enzymes, and the mechanism of biocatalysis regulation mediated by artificial cofactors are still unclear. Based on the previous work, this project aims to solve these existing problems in the field of artificial cofactors engineering through the interdisciplinary research of chemical biology, organic synthetic chemistry and protein engineering. This project will build several important types of artificial cofactor libraries and their regenerative modules, focuses on the recognition and regulation mechanism between artificial cofactors and enzymes, and develop the methods for the adaptation of artificial cofactor and enzyme and the intracellular transport pathways of artificial cofactors. Finally, this strategy will used for the industrial manufacture of several fine chemicals. This project will provide theoretical basis, technical reference and industrial demonstration for the biocatalytic process optimization and enhancement mediated by artificial cofactor-based control system.

我们前期的研究表明，通过对天然辅因子分子结构的改造，可有效的影响其催化性能，进而达到调控生物催化的目的，部分研究工作展现出了良好的工业化应用前景。然而目前对人工辅因子与酶相互识别作用的分子机制、及人工辅因子介导的生物催化调控机制尚不清晰。本项目拟在前期工作基础之上，针对人工辅因子领域现存的问题，通过化学生物学、有机合成化学及蛋白工程的学科交叉，系统的开展若干类重要的人工辅因子元件库及其再生模块的构建，重点揭示人工辅因子与酶识别作用的分子机制及其结构性质对生物催化调控的影响，探索人工辅因子与酶的适配改造手段及利用转运蛋白传送人工辅因子的体内传递途径，并最终将其应用于人工辅因子介导调控的若干种精细化学品的实际生产过程中，为基于人工辅因子调控的生物催化过程优化和强化提供理论基础、技术借鉴与工业示范。

本项目针对人工辅因子与酶相互识别作用的分子机制作用不明、及人工辅因子介导的生物催化调控机制作用不清等问题，在我们前期工作基础之上，通过化学生物学、有机合成化学及蛋白工程的学科交叉，系统的开展了人工黄素、人工烟酰胺等辅因子元件库及其再生模块的构建，重点揭示了人工辅因子与酶识别作用的分子机制及其结构性质对生物催化调控的影响，探索了人工辅因子与酶的适配改造手段及人工辅因子的胞内传递途径，并最终将其应用于人工辅因子介导的α-酮戊二酸、甘露糖、二羟基丙酮等精细化学品的实际制备过程中，为基于人工辅因子调控的生物催化过程优化和强化提供了理论基础与技术借鉴。