Generation and Reactivity of Reactive Sulfur Species

有了这个奖项，化学结构、动力学和机理b项目继续支持约翰·霍普金斯大学化学系约翰·托斯卡诺教授的工作。该研究将涉及生物相关活性硫物种的生成和反应性，包括氢过硫化物（RSSH）。硫化氢（H2S）是一种内源性小分子信号转导剂，其多种生理作用已被广泛报道。然而，造成这些影响的化学机制仍然没有得到充分的界定。最近的报道表明，H2S的大部分生物活性可能归因于RSSH， RSSH参与了蛋白质半胱氨酸残基（PSH）的修饰，生成蛋白质过硫化物（PSSH）。近年来，人们对这些物种的生理功能产生了浓厚的兴趣。例如，在阿尔茨海默氏症、帕金森氏症和亨廷顿氏症等神经系统疾病中，蛋白质过硫化已被证明是失调和减少的。这项研究将为研究生和本科生提供广泛而全面的培训，为他们将来在工业界和学术界的机会提供良好的服务。本科生参与研究将继续是重中之重，因为以前的学生表示，这段经历是他们大学生涯的亮点，有助于明确他们的兴趣，并为未来的学习做好准备。此外，还将为高中学生提供以化学/生物界面为重点的综合课后科学拓展体验。尽管越来越多的证据表明RSSH在生理氧化还原信号传导中的作用，但RSSH的生物学相关化学仍然相对知之甚少。预测RSSH生物学功能的一种方法是了解它们的基本化学成分。因此，研究的重点之一是进一步探索RSSH及其相关活性硫的基本化学性质。由于RSSH不稳定且分解迅速，因此很难在水溶液中进行研究，通常是在原位生成的。虽然已经报道了几种生成RSSH的策略，但仍然需要进一步开发用于生物应用的高效和受控生产RSSH的新方法。因此，还将评估新型RSSH光递质和蛋白质过硫试剂的开发，这些试剂设计用于与小分子硫醇清洁反应生成RSSH和蛋白质半胱氨酸残基生成PSSH。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 Chemical Structure, Dynamics & Mechanisms-B Program continues its support of the work of Professor John P. Toscano of the Chemistry Department at Johns Hopkins University. The research will involve the generation and reactivity of biologically relevant reactive sulfur species, including hydropersulfides (RSSH). Hydrogen sulfide (H2S) is an endogenously generated small molecule signaling agent whose diverse physiological effects have been well documented. The chemical mechanisms responsible for these effects, however, remain inadequately defined. Recent reports indicate that much of H2S biological activity may be attributed to RSSH, which have been reported to be involved in the modification of protein cysteine residues (PSH) to generate protein hydropersulfides (PSSH). Recently, there has been intense interest in the physiological functions of these species. For example, protein persulfidation has been shown to be dysregulated and reduced in neurological disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. The research will afford broad, comprehensive training for graduate students and undergraduates, serving them well for future opportunities in both industry and academia. Undergraduate participation in research will continue to be a high priority since previous students have indicated that this experience was the highlight of their college careers and was instrumental in clarifying their interests and preparing them for future studies. An integrated, after school science outreach experience for high school students focusing on the chemistry/biology interface will also be developed.Despite increasing evidence for the role of RSSH in physiological redox signaling, the biologically relevant chemistry of RSSH is still relatively poorly understood. One way to predict the biological functions of RSSH is to understand their fundamental chemistry. Thus, one focus of the proposed research is further exploration of the fundamental chemical properties of RSSH and related reactive sulfur species. Because RSSH are unstable and decomposes rapidly into a variety of species, they are inherently difficult to study in aqueous solution and are typically generated in situ. Although several strategies for RSSH generation have been reported, there is still an unmet need for the further development of new methods for the efficient and controlled production of RSSH for biological applications. Thus, the development of novel RSSH photoprecursors and protein persulfidating reagents, designed to react cleanly with small molecule thiols to produce RSSH and protein cysteine residues to produce PSSH, will also be evaluated.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.