Generation and Solution Reactivity of Small Molecule Sulfur-based Signaling Agents

约翰霍普金斯大学化学系John P. Toscano教授的研究获得了化学结构、动力学和机理b项目的支持。该研究涉及与生物相关的硫基小分子（如硫化氢（H2S）和过硫化物（RSSH））的生成和溶液反应性。硫化氢（H2S）是一种信号剂，其在体内的作用已被充分证明。例如，H2S在大脑中充当神经调节剂，可用于治疗神经退行性疾病，如帕金森病和阿尔茨海默病。造成这些影响的化学机制尚不清楚。最近的报告表明，硫化氢的生物活性实际上可能归因于氢过硫化物，因此这也将进行测试。该项目为研究生和本科生提供广泛而全面的培训，为他们未来在工业界和学术界的工作做好准备。马里兰州巴尔的摩市中学生的课后科学拓展体验正在开发中。氢过硫化物参与了几种酶和蛋白质的重要翻译后修饰。此外，小分子氢过硫化物，如半胱氨酸氢过硫化物和谷胱甘肽氢过硫化物，已在组织、细胞和血浆中检测到显著浓度。不幸的是，氢过硫化物本身就很难在水溶液中进行研究，因为它们不稳定，而且会迅速分解成各种各样的物质。因此，氢过硫化物通常是原地生成的。虽然已经报道了几种生成氢过硫化物的策略，但在没有外源试剂参与的情况下，开发有效和受控的氢过硫化物生产新方法的需求仍然没有得到满足。开发新型氢过硫前体和蛋白质过硫试剂是本项目的重点。先前的研究表明，另一种小分子生物信号剂硝基（氮杂酮，HNO）通过修饰蛋白质硫醇来激发其大部分活性。考虑到硫化氢和氢过硫化物的预期反应性，与HNO的反应是预期的，并且可能与观察到的生物反应有关。这一反应的机理和产生的产物将被深入研究。同样，硫化氢与HNO的反应也将被研究。这些反应的机制和产物，利用标准的分析工具以及膜入口质谱，将进行研究。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, and Mechanisms-B Program support of the research of Professor John P. Toscano of the Chemistry Department at Johns Hopkins University. The research involves the generation and solution reactivity of biologically-relevant, sulfur-based, small molecules such as hydrogen sulfide (H2S) and hydropersulfides (RSSH). Hydrogen sulfide (H2S) is a signaling agent whose effects in the body have been well documented. For example, H2S acts as a neuromodulator in the brain and may have applications in the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's disease. The chemical mechanisms responsible for these effects are poorly understood. Recent reports indicate that the biological activity of hydrogen sulfide may actually be attributed to hydropersulfides and so this will also be tested. The project gives broad, comprehensive training to both graduate and undergraduate students, preparing them for future jobs in both industry and academia. An afterschool science outreach experience for middle school students in Baltimore, MD is in development.Hydropersulfides are involved in important post-translational modifications in several enzymes and proteins. In addition, small molecule hydropersulfides such as cysteine hydropersulfide and glutathione hydropersulfide have been detected in tissues, cells, and plasma at significant concentrations. Unfortunately, hydropersulfides are inherently difficult to study in aqueous solution, as they are unstable and decomposes rapidly into a variety of species. As a result, hydropersulfides are typically generated in situ. Although several strategies for hydropersulfide generation have been reported, there is still an unmet need for the development of new methods for the efficient and controlled production of hydropersulfides without the involvement of exogenous reagents. The development of novel hydropersulfide precursors and protein persulfidating reagents is a focus of this project. Previous work has demonstrated that another small molecule biological signaling agent, nitroxyl (azanone, HNO), elicits much of its activity through modification of protein thiols. Given the expected reactivity of hydrogen sulfide and hydropersulfides, reaction with HNO is anticipated and may be relevant to the observed biological reactions. The mechanism of this reaction and the resulting products will be investigated thoroughly. Likewise, the reaction of hydrogen sulfide with HNO will also be examined. The mechanisms and products of these reactions, utilizing standard analytical tools as well as membrane inlet mass spectrometry, will be studied.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.