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，化学司的化学过程计划是为波士顿大学的Pinghua Liu博士提供资金，以表征催化Ergothioneine生物合成中C-S键形成的酶。尽管含硫分子（小分子和大分子）在生物系统中起着许多重要作用，硫代表了整个细胞干重的百分之一，迄今为止，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键形成反应在天然产物化学和机械酶学的边界。 对这些反应的细节的新洞察力可能对含硫分子的工业过程有下游应用。这项工作的跨学科性质为培训学生走向STEM职业而培训学生的平台是一个绝佳的平台。核心教育目标是学生学习如何将基础研究中获得的知识应用于解决现实世界问题。该奖项重点是酶在生物系统中催化的C-S键形成反应，特别是阐明了Ergothioneine的生物合成中C-S键形成的机制。这些反应是独一无二的，因为它们涉及未激活的SP2 C-H键，并且因为自然已经进化了两种不同的方法来激活该键以产生C-S键，一种有氧和另一种厌氧。 LIU团队将使用X射线结构确定，计算蛋白设计，非天然氨基酸诱变和动力学测量的工具，以深入了解这些酶介导的转换的机制。对于有氧途径，LIU博士系统地评估了关键的非血红素铁酶的结构 - 功能关系，该酶催化C-S键形成反应，并应用新知识以区分该反应的一些机械模型。对于厌氧途径，该研究的重点是研究C-S键形成反应的硫源的研究，并阐明了这些厌氧反应的生物学作用。这项奖项反映了NSF的法定任务，并被认为是通过基金会的知识功能和广泛的影响来评估CRETIRIA的评估，认为值得通过评估的支持。

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