Engineered oxidative enzymes as catalysts for the formation of quinone methides in integrated chemical synthesis.

工程氧化酶作为集成化学合成中形成醌甲基化物的催化剂。

• 批准号: 1869631
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1869631
• 关键词: Engineered; oxidative; enzymes; catalysts; formation

In synthetic chemistry, there has been increasing prominence in the use of engineered enzymes to execute chemical transformations. These biocatalysts are attractive since they offer highly efficient synthesis in terms of yields and selectivity, together with an inherent environmental sustainability stemming from a minimal reliance on halogenated or metallic feedstocks. In particular, there is currently great interest in the integration of biocatalytic reactions into larger multi-step synthetic schemes to enable the "telescoped" construction of molecules. This is an area that is of particular interest in chemical industries where there is a need for the rapid construction of complex molecules (e.g. pharmaceuticals, agrochemicals), yet research in this area is still in its infancy. For example, we have recently demonstrated the combination of two convergent biocatalytic reactions: a peroxidase-mediated oxidation of catechols to quinones, which is coupled with an aromatic amine that has undergone halogenase-catalysed bromination and/or chlorination - all in a single vessel.Of current particular interest is the in situ generation of o-quinone methides (QM), which are versatile intermediates in chemical synthesis. This project will aim to further explore the biocatalytic generation of these QMs and develop the "one-pot" reaction sequences, through modifications of the reaction conditions as well as the mutagenic engineering of the enzymes. Indeed, the development of engineered peroxidase enzymes that are particularly suited for synthetic chemistry will be a major goal of this project. For example, the development of enzymes that have a high redox potential (to enable the oxidation of unreactive aromatic compounds), and that are resistant to extremes of pH and high concentrations of organic solvents.The student will therefore work at the interface between organic chemistry (bioorganic chemistry) and molecular biology (enzymology). They will thus gain a wide range of expertise that are critical for the industrial biotechnology sector - the ability to rationally engineer new, high-value biocatalysts through fundamental insights in biomolecular structure and chemical reactivity.

在合成化学中，使用工程酶进行化学转化的情况越来越突出。这些生物催化剂很有吸引力，因为它们在产率和选择性方面提供了高效的合成，并具有固有的环境可持续性，这源于对卤化或金属原料的最小依赖。特别是，目前人们对将生物催化反应整合到更大的多步骤合成方案中以实现分子的“可伸缩”结构非常感兴趣。这是化学工业中特别感兴趣的一个领域，需要快速构建复杂分子(例如制药、农用化学品)，但这一领域的研究仍处于初级阶段。例如，我们最近展示了两个聚合生物催化反应的组合：过氧化物酶介导的儿茶酚氧化为苯二酚，它与经过卤代酶催化的溴化和/或氯化的芳香胺偶联-所有这些都在一个容器中进行。目前特别感兴趣的是原位生成邻苯二酚甲醚(QM)，这是化学合成中广泛使用的中间体。本项目旨在通过改变反应条件和酶的诱变工程，进一步探索这些QMS的生物催化生成，并开发“一锅”反应序列。事实上，开发特别适合于合成化学的工程过氧化物酶将是该项目的主要目标。例如，开发具有高氧化还原潜力(能够氧化非活性芳香化合物)，并能抵抗极端pH和高浓度有机溶剂的酶。因此，学生将从事有机化学(生物有机化学)和分子生物学(酶学)之间的研究。因此，他们将获得对工业生物技术部门至关重要的广泛专业知识--通过对生物分子结构和化学反应的基本见解，合理设计新的、高价值生物催化剂的能力。