The Bioorganic Chemistry of Electrophilic Sulfur in Cysteine Post-Translational Modifications

半胱氨酸翻译后修饰中亲电硫的生物有机化学

• 批准号: 2313438
• 负责人: Kate Carroll
• 金额: $ 49.96万
• 依托单位: University of Florida
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2313438&HistoricalAwards=false
• 关键词: Bioorganic; Chemistry; Electrophilic; Sulfur; Cysteine

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professor Kate Carroll from the University of Florida will investigate post-translational protein cysteine modifications. Cysteine plays essential roles in protecting the cell from oxidative damage through its thiol functional group. The importance of thiol modifications has been recognized by chemists and biologists alike, however, their impact on the chemical reactivity of sulfur has not been systematically studied until now. Through synthesis and physical-organic characterization, Dr. Carroll’s research explores how different cysteinyl thiol group modifications endow the sulfur atom with distinct chemical properties. This research will allow graduate students to gain specialized training in organosulfur chemistry and effective protein bioconjugation strategies. This project will also be integrated into an outreach program to introduce high school and undergraduate students to the science of bioorthogonal reactions.This research project seeks to expand the fundamental science of electrophilic sulfur chemistry. The reactivity of electrophilic sulfur species are being investigated by kinetic and thermodynamic evaluation of models using time-resolved nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Reactivity is to be studied by generating small molecule models using advanced methods and new reactions in organosulfur chemistry. A range of post-translational thiol modifications identified as central to reversible redox regulation in biology are being targeted for study. The sulfur-based functionalities to be studied include cyclic sulfenamides, polarized disulfides, and S-sulfonates. Information gleaned from these studies is expected to provide both mechanistic guidance and new research tools in support of the investigation of protein cysteine oxidation-reduction chemistry in biology, particularly in dynamic redox environments.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.

在化学系生命过程化学（CLP）项目的支持下，佛罗里达大学的 Kate Carroll 教授将研究翻译后蛋白质半胱氨酸修饰在保护细胞免受氧化方面发挥的重要作用。硫醇修饰的重要性已得到化学家和生物学家的认可，但是迄今为止，它们对硫化学反应性的影响尚未通过合成和系统研究。卡罗尔博士的研究探索了不同的半胱氨酰硫醇基团修饰如何赋予硫原子不同的化学性质，该研究将使研究生获得有机硫化学和有效蛋白质生物共轭策略方面的专门培训。进入一个推广计划，向高中生和本科生介绍生物正交反应科学。该研究项目旨在扩展亲电硫化学的基础科学。正在使用时间分辨核磁共振（NMR）光谱和质谱（MS）对模型进行动力学和热力学评估来研究硫物质，并通过使用有机硫化学中的先进方法和新反应生成小分子模型来研究反应性。一系列被认为是生物学中可逆氧化还原调节核心的翻译后硫醇修饰正在成为研究的目标，其中包括环状功能。从这些研究中收集的信息有望提供机制指导和新的研究工具，以支持生物学中蛋白质半胱氨酸氧化还原化学的研究，特别是在动态氧化还原环境中。授予 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。