Molecular basis for enzymatic control of enantiodivergent Diels-Alder reactions in spirotetronate biosynthesis

螺体酯生物合成中对映体发散狄尔斯-阿尔德反应酶促控制的分子基础

• 批准号: 2097255
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2097255
• 关键词: Molecular; basis; enzymatic; control; enantiodivergent

Chemical synthesis of complex molecules with applications in medicine, animal health and agriculture is often inefficient and cumbersome, with problems including poor overall product yields, difficulties with scale-up and heavy reliance on non-renewable resources. Harnessing natural product biosynthetic enzymes is a promising strategy for more sustainable, scalable and efficient production of complex molecules. However, a detailed molecular understanding of the catalytic mechanisms of such enzymes is required to achieve this. This project aims to develop a better understanding of how Diels-Alderase enzymes that catalyse key [4+2] cycloaddition reactions in the biosynthesis of spirotetronate natural products control the stereochemistry of their products. A highly interdisciplinary approach combining synthesis of substrates and substrate analogues with enzymology, analytical chemistry, structural biology, site-directed mutagenesis and docking simulations will be employed . The outcomes of this work will underpin future efforts to exploit enzymes that catalyse complexity-generating transformations, such as Diels-Alder [4+2] cycloadditions, for more sustainable production of structurally complex molecules.

在医药、动物健康和农业中应用的复杂分子的化学合成通常效率低下且繁琐，存在的问题包括总体产品产量低、难以扩大规模以及严重依赖不可再生资源。利用天然产物生物合成酶是更可持续、可扩展和有效生产复杂分子的有前途的策略。然而，要实现这一点，需要对这些酶的催化机制进行详细的分子理解。该项目旨在更好地了解催化螺丁酮天然产物生物合成中关键[4+2]环加成反应的狄尔斯-阿尔德酶如何控制其产物的立体化学。将采用高度跨学科的方法，将底物和底物类似物的合成与酶学，分析化学，结构生物学，定点诱变和对接模拟相结合。这项工作的成果将支持未来的努力，利用酶催化复杂性产生的转换，如狄尔斯-阿尔德[4+2]环加成，更可持续地生产结构复杂的分子。