Expanding the chemistry of life: New enzymatic platforms for synthesis of bioactive organofluorines

扩展生命化学：用于合成生物活性有机氟的新酶平台

• 批准号: 10308388
• 负责人: Xiongyi Huang
• 金额: $ 24.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308388
• 关键词: Alkenes; Anabolism; Attenuated; Benign; Binding; Binding Proteins; Biochemistry; Biology; Carbon; Chemicals; Chemistry; Complex; Coupled; Development; Directed Molecular Evolution; Drug Industry; Electron Spin Resonance Spectroscopy; Electrons; Engineering; Enzymatic Biochemistry; Enzymes; Epoxy Compounds; Exhibits; FDA approved; Fluorides; Fluorine; Heme; Hemeproteins; Hydration status; Hydrogen Bonding; Investigation; Iron; Kinetics; Lead; Life; Mediating; Medical; Mentors; Metabolism; Methods; Modernization; Mossbauer Spectroscopy; Mutation; Natural Products; Nature; Organic Chemistry; Oxygenases; Pathway interactions; Pharmacologic Substance; Phase; Positioning Attribute; Positron-Emission Tomography; Property; Protein Engineering; Proteins; Reaction; Research; Route; Scaffolding Protein; Specificity; System; Techniques; Therapeutic; Water; X-Ray Crystallography; analog; base; carbene; catalyst; combinatorial; cost effective; cyclopropane; drug development; enzyme activity; insight; oxidation; radiotracer; scaffold; simulation; stop flow technique

Project Summary/Abstract Enzymes are well known for catalyzing chemical transformations with exquisite specificity and selectivity under environmentally benign conditions. Thus, there is a continuing need for the development of new enzymes that can effect critical synthetic transformations. One important type of transformations that is rarely present in current catalytic repertoire of biology is reactions for synthesis of organofluorine compounds. Organofluorine molecules have assumed a privileged position in modern pharmaceutical industry, which comprise ~ 30% of all pharmaceuticals and ~ 60% of all FDA-approved radiotracers for positron emission tomography (PET). The focus of this proposal is to generate new enzymatic platforms for the synthesis of organofluorine molecules. With protein engineering techniques like directed evolution, we will bring fluorination activities into existing proteins that share mechanistic features with synthetic fluorination reactions. These enzymatic platforms will expand the chemical space of biosynthesis tremendously and open up possibilities to develop whole new biosynthetic pathways for organofluorine synthesis. On their own, the enzymes developed would lead to highly efficient and selective synthetic routes to organofluorines that are currently unobtainable or feasible at scale. The structural and kinetic investigations of these new enzymes will greatly extend our understanding of enzymology and biochemistry to catalytic reactions unprecedented in nature. These new fluorination enzymes could be genetically incorporated into living hosts and coupled with existing biosynthetic pathways, enabling specific incorporation of fluorine groups into complex bioactive molecules. These research efforts will empower the development of new fluorine-based therapeutics and provide a paradigm for bringing non-biological chemistries to life.

项目总结/摘要 众所周知，酶在催化化学转化时具有精确的特异性和选择性， 环境友好的条件。因此，持续需要开发新的酶， 可以影响关键的合成转化一种重要的转换类型，在当前的 生物学的催化体系是合成有机氟化合物的反应。有机氟分子 在现代制药业中占据了特权地位，占所有制药行业的30%左右。 药物和~ 60%的FDA批准的用于正电子发射断层扫描（PET）的放射性示踪剂。重点 该提议的一个重要目的是产生用于合成有机氟分子的新的酶平台。与 蛋白质工程技术，如定向进化，我们将把生物活性引入现有的蛋白质中， 它们与合成的反硝化反应具有相同的机理特征。这些酶平台将扩大 生物合成的化学空间巨大，并开辟了开发全新生物合成的可能性 有机氟合成的途径。就其本身而言，所开发的酶将导致高效， 有机氟的选择性合成路线目前无法获得或在规模上可行。结构性 对这些新酶的动力学研究将大大扩展我们对酶学的理解， 生物化学催化反应的性质前所未有的。这些新的酶可能是 基因整合到活的宿主中，并与现有的生物合成途径相结合， 将氟基团并入复杂的生物活性分子中。这些研究工作将使 开发新的氟基疗法，并提供一种将非生物化学 生命

项目成果

Selective CH bond functionalization with engineered heme proteins: new tools to generate complexity.

• DOI: 10.1016/j.cbpa.2018.10.004
• 发表时间: 2019-04
• 期刊: Current opinion in chemical biology
• 影响因子: 7.8
• 作者: Zhang RK;Huang X;Arnold FH
• 通讯作者: Arnold FH

Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer.

• DOI: 10.1002/anie.202208936
• 发表时间: 2022-12
• 期刊: Angewandte Chemie
• 作者: Lucas Schaus;Anuvab Das;A. M. Knight;Gonzalo Jiménez‐Osés;K. Houk;M. Garcia‐Borràs;F. Arnold;Xiong Huang