Generation and Reactivity of Reactive Sulfur Species

Johns Hopkins University, Baltimore MD

Investigators

Abstract

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.