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

基本信息

批准号：
10065508
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
项目类别：
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/10065508
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 Structure 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

项目摘要

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.

项目摘要/摘要酶以催化化学转化而具有精致的特异性和选择性而闻名环境良性条件。因此，持续需要开发新酶可以影响关键的合成转换。当前很少存在的一种重要类型的转换类型生物学的催化曲目是有机氟化化合物合成的反应。有机氟分子已经在现代制药行业中担任特权职位，其中约有30％所有FDA批准的放射性示踪器（PET）的药物和所有FDA批准的放射性示例中的约60％。重点该建议的是生成新的酶促平台，以合成有机氟分子。和蛋白质工程技术（如定向进化），我们将将氟化活性带入现有蛋白质这种具有合成氟化反应的机械特征。这些酶平台将扩展生物合成的化学空间非常大，并为开发全新的生物合成的可能性开辟了可能性有机氟合成的途径。自行开发的酶会导致高效，并且有选择性的合成途径到当前无法体现或可行的有机荧光素途径。结构对这些新酶的动力学研究将极大地扩展我们对酶学和对催化反应的生物化学本质上是前所未有的。这些新的氟化酶可能是遗传纳入活宿主，并与现有的生物合成途径相结合，使特定将氟基团掺入复杂的生物活性分子中。这些研究工作将增强开发新的基于氟的疗法，并为带来非生物化学的范例提供了范式生命。