Mechanistic Studies of C-X Bond Formation Chemistries

C-X 键形成化学的机理研究

• 批准号: 2004109
• 负责人: Pinghua Liu
• 金额: $ 42万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2004109&HistoricalAwards=false
• 关键词: Mechanistic; Studies; Bond; Formation; Chemistries

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Pinghua Liu from Boston University to characterize the enzymes that catalyze the formation of C-S bonds in the ergothioneine biosynthesis. Although sulfur-containing molecules, both small molecules and macromolecules, play many important roles in biological systems and sulfur represents one percent of the entire cell dry weight, to date, details of the biosynthesis of the vast majority of sulfur-containing molecules are still missing. Hence, C-S bond formation reactions are at the frontier of natural product chemistry and mechanistic enzymology. New insight into the details these reactions may have downstream applications to industrial processes for the synthesis of sulfur-containing molecules. The interdisciplinary nature of the work renders it an excellent platform to train students on the path to STEM careers. The central educational objective is that students learn how to apply knowledge gained in basic research to solve real world problems.This award focuses on the C-S bond formation reactions catalyzed in biological systems by enzymes,specifically on the elucidation of the mechanism of C-S bond formation in the biosynthesis of ergothioneine. These reactions are unique because they involve an unactivated sp2 C-H bond and because nature has evolved two different ways to activate this bond to produce a C-S bond, one aerobic and another anaerobic. The Liu team will use the tools of x-ray structure determination, computational protein design, unnatural amino acid mutagenesis, and kinetic measurements to gain insight into the mechanism of these enzyme-mediated transformations. For the aerobic pathway, Dr. Liu systematically evaluates structure-function relationships for key non-heme iron enzymes that catalyze C-S bond formation reactions and applies the new knowledge to differentiate among a few mechanistic models for the reaction. For the anaerobic pathway, the research focuses on the study of the source of sulfur for the C-S bond formation reactions and the elucidation of the biological role of these anaerobic reactions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，化学部的生命过程化学项目资助波士顿大学的刘平华博士，以表征在麦角硫因生物合成中催化C-S键形成的酶。虽然含硫分子，无论是小分子还是大分子，在生物系统中发挥着许多重要作用，并且硫占整个细胞干重的1%，但迄今为止，绝大多数含硫分子的生物合成的细节仍然缺失。 因此，C-S键形成反应处于天然产物化学和机械酶学的前沿。 对这些反应细节的新认识可能在含硫分子合成的工业过程中具有下游应用。工作的跨学科性质使其成为培养学生走上STEM职业道路的绝佳平台。中心教育目标是学生学习如何应用基础研究中获得的知识来解决真实的世界问题。该奖项侧重于生物系统中酶催化的C-S键形成反应，特别是阐明麦角硫因生物合成中C-S键形成的机制。这些反应是独特的，因为它们涉及未活化的sp2 C-H键，并且因为自然界已经进化出两种不同的方式来活化这种键以产生C-S键，一种是需氧的，另一种是厌氧的。Liu团队将使用X射线结构测定，计算蛋白质设计，非天然氨基酸诱变和动力学测量等工具来深入了解这些酶介导的转化机制。对于有氧途径，刘博士系统地评估了催化C-S键形成反应的关键非血红素铁酶的结构-功能关系，并应用新知识来区分反应的几种机制模型。在厌氧途径方面，研究重点是C-S键形成反应的硫源的研究，以及这些厌氧反应的生物学作用的阐明。该奖项反映了NSF的法定使命，通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Light-driven Oxidative Demethylation Reaction Catalyzed by a Rieske-type Non-heme Iron Enzyme Stc2.

Rieske型非血红素铁酶Stc2催化的光驱动氧化去甲基化反应。

• DOI: 10.1021/acscatal.2c04232
• 发表时间: 2022
• 期刊: ACS catalysis
• 影响因子: 12.9
• 作者: Hu,Wei-Yao;Li,Kelin;Weitz,Andrew;Wen,Aiwen;Kim,Hyomin;Murray,JessicaC;Cheng,Ronghai;Chen,Baixiong;Naowarojna,Nathchar;Grinstaff,MarkW;Elliott,SeanJ;Chen,Jie-Sheng;Liu,Pinghua
• 通讯作者: Liu,Pinghua