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.

在化学过程（CLP）方案的支持下，佛罗里达大学的凯特·卡罗尔（Kate Carroll）教授将调查翻译后蛋白质半胱氨酸修饰。半胱氨酸在保护细胞免受其硫醇官能团免受氧化损伤免受氧化损伤方面起着重要作用。化学家和生物学家都认识到硫醇修饰的重要性，但是，直到现在，它们对硫的化学反应性的影响还没有系统地研究。通过合成和物理有机表征，Carroll博士的研究探讨了不同的半胱氨酸硫醇组修饰如何赋予硫原子具有不同的化学特性。这项研究将使研究生能够获得有机硫化学和有效蛋白质生物缀合策略的专门培训。该项目还将集成到一项外展计划中，以将高中和本科生介绍生物正交反应科学。本研究项目旨在扩大亲电硫化学的基本科学。通过使用时间分辨的核磁共振（NMR）光谱和质谱法（MS）对模型的动力学评估和热力学评估，正在研究亲电硫的反应性。反应性是通过使用高级方法和有机硫化学中的新反应产生小分子模型来研究的。一系列针对生物学中可逆氧化还原调节的一系列翻译后硫醇修饰是针对研究的。要研究的基于硫的功能包括循环磺酰胺，偏振二硫化物和S-磺酸盐。这些研究收集的信息有望提供机械指导和新的研究工具，以支持对生物学中蛋白质半胱氨酸氧化减少化学的研究，尤其是在动态氧化还原环境中。这项奖项反映了NSF的法定任务，并通过使用该基金会的智力优点和广泛的影响来评估NSF的法定任务。