Mechanistic Studies of C-X Bond Formation Chemistries

凭借这一奖项，化学学部生命过程化学项目资助了波士顿大学刘平华博士，以表征麦角硫因生物合成中催化C-S键形成的酶。虽然含硫分子，包括小分子和大分子，在生物系统中扮演着许多重要的角色，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制酶学的前沿。对这些反应细节的新见解可能在含硫分子合成的工业过程中有下游应用。这项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。教育的中心目标是让学生学会如何运用在基础研究中获得的知识来解决现实世界的问题。该奖项主要关注酶在生物系统中催化的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，因为它们涉及一个未激活的sp2碳氢键，因为大自然已经进化出两种不同的方式来激活这个键来产生一个碳- s键，一种是有氧的，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、非自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转化的机制。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，并应用新知识区分反应的几种机制模型。对于厌氧途径，研究重点是研究C-S键形成反应的硫源，并阐明这些厌氧反应的生物学作用。该奖项反映了美国国家科学基金会的法定使命，并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。

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.