An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis

用于立体选择性自由基生物催化的可进化金属酶平台

• 批准号: 10650814
• 负责人: Yang Yang
• 金额: $ 36.59万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650814
• 关键词: Aromatic Compounds; Biochemical; Biochemistry; Catalysis; Computer Models; Data; Development; Engineering; Enzymes; Laboratories; Mediating; Metalloproteins; Methods; Nature; Nitrogen; Organic Chemistry; Organometallic Chemistry; Outcome; Oxidation-Reduction; Process; Property; Reaction; Science; Technology; Therapeutic; clinically significant; interdisciplinary approach; metalloenzyme; novel; programs; small molecule

Project Summary Despite substantial advancements in small-molecule catalysis, general methods to control the stereoselectivity in radical-mediated transformations remain a formidable challenge facing synthetic chemists. On the other hand, enzymes are known for their ability to exert exquisite control over the stereochemical outcome of the reactions they catalyze. However, the catalytic repertoire of enzymes has been largely limited to their native biochemistry. Using an interdisciplinary approach combining ideas and technologies from organic chemistry, organometallic chemistry, biocatalysis, enzyme engineering and computational modeling, we will reprogram naturally occurring metalloenzymes to catalyze unnatural radical reactions with excellent stereoselectivity. Capitalizing on the innate redox property of metallocofactor present in a plethora of natural metalloproteins, we will develop metalloredox radical biocatalytic reactions with significant synthetic utility. First, we will develop new-to-nature metalloredox atom transfer radical addition reactions that proceed with excellent diastereo- and enantiocontrol. Second, we will advance stereoselective radical additions to aromatic compounds in a metalloenzyme-controlled fashion. Furthermore, enantioselective C-H functionalization reactions involving metalloenzymatically formed nitrogen- centered radicals will be developed. All the three aims are supported by strong preliminary data gathered in our laboratory. Together, these novel metalloredox biocatalytic processes constitute a powerful toolbox for the rapid assembly of diverse bioactive small molecules that are highly valuable in biomedical sciences. Furthermore, the development of new-to-nature catalytic functions will dramatically broaden the biochemical landscape of metalloenzymes.

项目摘要 尽管在小分子催化中取得了重大进步，但控制立体选择性的一般方法 在自由基介导的转化中，合成化学家面临着巨大的挑战。另一方面， 酶以其对反应的立体化学结果的精致控制的能力而闻名 他们催化。但是，酶的催化曲目在很大程度上仅限于其本地生物化学。 使用跨学科方法结合了有机化学的思想和技术，有机金属 化学，生物催化，酶工程和计算建模，我们将自然进行重新编程 金属酶以极好的立体选择性催化不自然的自由基反应。利用先天 金属蛋白质中存在的金属生产剂的氧化还原特性，我们将开发金属氧化物 具有显着合成效用的自由基生物催化反应。首先，我们将开发新的金属氧 原子转移自由基添加反应，以极好的非对映射和对映射进行。第二，我们 将以金属酶控制的方式推进对芳族化合物的立体选择性添加。 此外，对映选择性的C-H官能化反应涉及金属酶形成的氮 将开发中心的自由基。所有三个目标都得到了我们收集的强大初步数据的支持 实验室。这些新颖的金属氧化物生物催化过程共同构成了快速的强大工具箱 在生物医学科学中高度有价值的不同生物活性小分子的组装。此外， 开发新的催化功能将极大地拓宽 金属酶。