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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：
10044755
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/10044755
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.

项目总结/文摘