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

项目摘要/摘要 众所周知，酶催化化学转化具有极高的特异性和选择性 环境友好的条件。因此，对开发新的酶有持续的需求 可以影响关键的合成转化。当前很少出现的一种重要的转换类型 生物催化体系是合成有机氟化合物的反应。有机氟分子 在现代制药行业占据了特权地位，占所有制药行业的30%左右 药品和~60%FDA批准的用于正电子发射断层扫描(PET)的放射性示踪剂。焦点 这一建议的目的是为合成有机氟分子生成新的酶平台。使用 蛋白质工程技术，如定向进化，我们将在现有蛋白质中引入氟化活性 这与合成氟化反应具有共同的机理特征。这些酶平台将扩大 巨大的生物合成化学空间，为开发全新的生物合成开辟了可能性 有机氟合成途径。就其本身而言，开发的酶将导致高效和 有机氟的选择性合成路线，目前无法获得或规模化可行。结构性的 对这些新酶的动力学研究将极大地扩展我们对酶学和 生物化学催化反应在自然界是史无前例的。这些新的氟化酶可能是 将基因整合到活的宿主中，并与现有的生物合成途径结合，使特定的 将氟基团掺入复杂的生物活性分子中。这些研究工作将使 以氟为基础的新疗法的开发，并提供了一种非生物化学的范例 为生活！干杯。

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.