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

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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.