Unlocking New Chemistries in Extant Enzymes for Synthesizing Bioactive Molecules

项目摘要/摘要： 酶在其大分子结构的支持下，能够以精致的方式催化化学转化 控制，提供高选择性的产品。然而，酶可以支持的机制是 有限，使化学技术往往是首选的合成方法，而不考虑成本、毒性和 环境负担。这里有两个建议来扩大酶的活性，使之超越它们的自然功能 用于合成医学上重要的官能团。具体地说，血红素酶和蛋氨酸亚砜 还原酶首次被赋予分别执行胺化和氧化的任务，目的是 合成手性三氟乙胺、亚硫醚和亚磺亚胺，已知的赋予功能和药物的基序。 就像治疗学和临床候选人的特性一样。通过改造酶来催化超越 他们的自然能力，我们正在大胆地突破生物和化学的界限。这项创新具有 有可能彻底改变我们制造分子的方式，并引入新的化学反应 在活体中进行的。此外，这些努力将揭开生物催化领域前所未有的活动， 扩大了基因编码的化学转化的曲目。这项提议的成功将 提供高价值的分子和生物可再生催化剂，可能导致新药和 生物调控战略，最终目标是告知和改善人类健康。

Project Summary/Abstract: Enzymes, supported by their macromolecular structure, can catalyze chemical transformations with exquisite control, delivering products with high selectivity. The mechanisms that enzymes can support, however, are limited, making chemical technologies often the preferred method for synthesis, regardless of cost, toxicity, and environmental burden. Herein are two proposals to expand the activity of enzymes beyond their natural function for synthesizing medicinally important functional groups. Specifically, heme enzymes and methionine sulfoxide reductases are tasked for the first time with performing aminations and oxidations, respectively, toward synthesizing chiral trifluoroethylamines, sulfoxides, and sulfoximines, motifs known to bestow function and drug- like properties to therapeutics and clinical candidates. By engineering enzymes to catalyze reactions beyond their natural capabilities, we are boldly pushing the boundaries of biology and chemistry. This innovation has the potential to revolutionize the way we make molecules and introduce new chemical reactions that can be performed in living organisms. Furthermore, these efforts will unlock activities never before seen in biocatalysis, expanding the repertoire of genetically encoded chemical transformations. The success of this proposal will afford high-value molecules and biorenewable catalysts that may lead to the discovery of new medicines and strategies to regulate biology, with the ultimate objective of informing and improving human health.