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

在化学系生命过程化学(CLP)项目的支持下，佛罗里达大学的凯特·卡罗尔教授将研究蛋白质半胱氨酸翻译后修饰。半胱氨酸通过其硫醇官能团在保护细胞免受氧化损伤方面起着至关重要的作用。硫醇修饰的重要性已经得到了化学家和生物学家的一致认可，但它们对硫磺化学反应活性的影响直到现在还没有得到系统的研究。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酸硫醇基团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能够获得有机硫化学和有效的蛋白质生物结合策略方面的专门培训。这个项目还将被整合到一个推广计划中，向高中生和本科生介绍生物正交反应的科学。这个研究项目寻求扩大亲电硫磺化学的基础科学。利用时间分辨核磁共振(核磁共振)谱和质谱学(MS)对模型进行了动力学和热力学评估，研究了亲电硫物种的反应性。反应性的研究是通过使用先进的方法和有机硫化学中的新反应产生小分子模型来进行的。一系列翻译后硫醇修饰被认为是生物学中可逆氧化还原调节的核心，正在成为研究的目标。要研究的硫基官能团包括环亚硫酰胺、极化二硫化物和S磺酸盐。从这些研究中收集的信息有望提供机械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，特别是在动态的氧化还原环境中。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.