Discovery and Application of New Halogenases

新型卤化酶的发现及应用

• 批准号: 10581996
• 负责人: MICHELLE C CHANG
• 金额: $ 5.89万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581996
• 关键词: Binding Proteins; Biological; Catalysis; Chemicals; Complex; Development; Engineering; Enzymes; Family; Generations; Goals; Halogens; Health; Human; Hydrogen Bonding; In Vitro; Molecular; Natural Products; Positioning Attribute; Reaction; Structure; catalyst; chemical function; functional group; in vivo; insight; novel; public health relevance; scaffold; small molecule; tool

Project Summary The rapid and modular generation of molecular diversity is key to the search for new chemical functions. One particularly useful functional group is the halogen (X = Cl, Br, I), which enables many selective and effective downstream strategies for creating structural complexity. In this regard, halogenase enzymes have provided an important and complementary approach to synthetic catalysts for regio- and stereoselective introduction of a halogen substituent on a complex scaffold. While many families of halogenases exist, the radical halogenases provide the greatest potential for reaction diversity, as they are competent to replace unactivated C-H bonds with a halogen unlike those that operate by electrophilic or nucleophilic mechanisms. However, the substrate scope of these enzymes has been limited to date to either protein- bound substrates or large late-stage natural product intermediates. Our group has discovered a new clade of radical halogenases capable of reacting with small molecule substrates. We now seek to take advantage of this discovery to develop new tools for in vitro and in vivo synthesis. Specific aims of this proposal include: (i) elucidating the structure and mechanism of these new radical halogenases, which will provide important insight into their engineering, (ii) investigating and engineering selectivity in halogenases.

项目摘要 分子多样性的快速和模块化生成是寻找新化学功能的关键。 一种特别有用的官能团是卤素（X = Cl、Br、I），其使得能够实现许多选择性和非选择性的官能团。 有效的下游战略，以创造结构的复杂性。在这方面，卤化酶具有 为区域和立体选择性的合成催化剂提供了重要的补充方法。 在复杂支架上引入卤素取代基。虽然存在许多卤化酶家族，但它们都是卤化酶。 自由基卤化酶提供了反应多样性的最大潜力，因为它们能够取代 未活化的C-H键与卤素，不像那些通过亲电或亲核操作 机制等然而，迄今为止，这些酶的底物范围仅限于蛋白质- 结合底物或大的后期天然产物中间体。我们的团队发现了一个新的分支 能够与小分子底物反应的自由基卤化酶。我们现在想利用 利用这一发现，开发了用于体外和体内合成的新工具。本提案的具体目标 包括：（i）阐明这些新的自由基卤代酶的结构和机制，这将提供 重要的洞察他们的工程，（ii）调查和工程选择性卤化酶。