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，来自佛罗里达大学的Kate卡罗尔教授将研究翻译后蛋白质半胱氨酸修饰。半胱氨酸通过其巯基官能团在保护细胞免受氧化损伤中起重要作用。巯基修饰的重要性已经被化学家和生物学家所认识，然而，它们对硫的化学反应性的影响迄今为止尚未得到系统的研究。通过合成和物理有机表征，卡罗尔博士的研究探索了不同的半胱氨酰巯基修饰如何赋予硫原子不同的化学性质。这项研究将使研究生获得有机硫化学和有效的蛋白质生物缀合策略的专业培训。该项目还将整合到一个推广计划，向高中生和本科生介绍生物正交反应的科学。该研究项目旨在扩大亲电硫化学的基础科学。使用时间分辨核磁共振（NMR）光谱和质谱（MS）的模型的动力学和热力学评价的亲电硫物种的反应性进行了研究。反应性是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的。一系列翻译后巯基修饰被确定为生物学中可逆氧化还原调节的核心，正在成为研究的目标。 待研究的硫基官能团包括环状次磺酰胺、极化二硫化物和S-磺酸盐。从这些研究中收集到的信息有望为支持生物学中蛋白质半胱氨酸氧化还原化学的研究提供机制指导和新的研究工具，特别是在动态氧化还原环境中。该奖项反映了NSF的法定使命，并被认为值得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来支持。