Multifunctional Peroxygenase Catalysis for Synthetic Chemistry

合成化学中的多功能过氧化酶催化

• 批准号: EP/X014886/1
• 负责人: Gideon Grogan
• 金额: $ 69.32万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX014886%2F1
• 关键词: Multifunctional; Peroxygenase; Catalysis; Synthetic; Chemistry

Context of the research: Chemical reactions that add oxygen atoms to molecules (oxidations) are significant for industrial pharmaceutical production but often use harsh reaction conditions or toxic chemical reagents. Enzymes, however, operate under mild, non-toxic conditions to achieve equivalent, and often superior outcomes. Some enzymatic oxidations exploit enzymes called cytochromes P450 ('P450s' or 'CYPs'), which, while selective in their reactions, are also complex, unstable and have poor activity, militating against their application in industry. An alternative family of oxidation enzymes called 'Unspecific Peroxygenases' (UPOs) has recently been discovered that have far superior catalytic performance in terms of stability, activity and simplicity, and they thus have great potential for application in industrial oxidations. In addition to oxidations, we have recently found out that UPOs are also able to catalyze many other chemical reactions owing to a catalytically versatile iron atom on their active site. The application of UPOs to reactions other than oxidation would be very valuable for the development of sustainable reactions in synthetic chemistry outside the field of simply oxidation. Aims and Objectives: The aim of this project is to explore the applicability of UPOs in synthetic chemistry using a mixture of synthetic chemistry, enzymology, protein engineering and process chemistry. We will clone and express a library of UPOs from a range of organisms and characterise their activities and structures using biochemical methods. We will synthesise a range of precursor molecules against which we will test our new enzymes for a range of non-natural synthetic reactions. We will select the best enzymes and use protein engineering techniques to improve them. We will then apply these improved enzymes in scaled up synthetic reactions to provide valuable molecules of relevance to the pharmaceutical industry. In collaboration with industrial partner GSK, we will use the information gained from the project to provide UPOs tailored for non-natural chemistry for industrial applications.Applications and benefits: The applications of the research will be in the selective transformations of a range of organic substrates to both furnish intermediates and also catalyse late-stage modification of organic molecules for the production of bioactive compounds. The benefits of creating and applying libraries of adaptable enzyme catalysts will be more selective and sustainable chemical processes for applications in industrial chemistry, and especially in pharmaceutical production.

研究背景：将氧原子添加到分子中的化学反应（氧化）对于工业制药生产是重要的，但通常使用苛刻的反应条件或有毒的化学试剂。然而，酶在温和、无毒的条件下工作，以实现等同的，并且通常是上级的结果。一些酶促氧化利用称为细胞色素P450（“P450”或“CYP”）的酶，其虽然在其反应中具有选择性，但也是复杂的、不稳定的并且具有差的活性，从而妨碍其在工业中的应用。最近发现了一种称为“非特异性过氧化物酶”（UPO）的氧化酶家族，其在稳定性、活性和简单性方面具有远为上级的催化性能，因此它们在工业氧化中具有巨大的应用潜力。除了氧化，我们最近发现UPO还能够催化许多其他化学反应，这是由于其活性部位上的催化多功能铁原子。UPOs在氧化反应以外的反应中的应用对于在简单氧化领域之外的合成化学中发展可持续的反应是非常有价值的。宗旨和目标：该项目的目的是探索UPO在合成化学中的适用性，使用合成化学，酶学，蛋白质工程和工艺化学的混合物。我们将从一系列生物体中克隆和表达UPOs文库，并使用生物化学方法研究其活性和结构。我们将合成一系列的前体分子，我们将测试我们的新酶的一系列非天然合成反应。我们将选择最好的酶，并使用蛋白质工程技术来改善它们。然后，我们将在放大的合成反应中应用这些改进的酶，以提供与制药工业相关的有价值的分子。通过与工业合作伙伴GSK的合作，我们将利用从该项目中获得的信息，为工业应用提供针对非天然化学的UPO。应用和效益：该研究的应用将是一系列有机底物的选择性转化，以提供中间体，并催化有机分子的后期修饰，以生产生物活性化合物。创建和应用适应性酶催化剂库的好处将是更具选择性和可持续性的化学过程，用于工业化学，特别是制药生产。