Expanding the reactive sulfur species metabolome : characterization of small oxoacids of sulfur and hydrogen sulfide within in vitro and in vivo models and use of the ionophore thiomaltol to target melanoma in a copper-dependent mechanism.


Access rights

No access – contact librarywebmaster@baylor.edu

Journal Title

Journal ISSN

Volume Title



Hydrogen sulfide (H2S) is an endogenously produced signaling molecule with vast regulatory function in cardiovascular physiology controlling vasodilation, amelioration of hypoxia, and blood pressure. While the enzyme systems responsible for hydrogen sulfide generation are well-characterized, the mechanism of hydrogen sulfide inducing physiological change is poorly understood. This work shows hydrogen sulfide (H2S) and oxoacids of sulfur (SOS) consisting of sulfenic acid (HSOH) and sulfoxylic acid (HOSOH) are generated endogenously in a variety of different cultured cell lines including human cancer and primary cell lines as well as bacterial and yeast cells. The methodology used involves a novel derivatization and LCMS metabolomics methodology, adapted from well-known protein trapping strategies. Steady-state measurements of both endogenous concentrations and efflux concentrations are reported as well as changes seen under hydrogen sulfide producing enzyme inhibition and hypoxia. Finally, the LCMS-derivatization methodology described for in vitro work was translated to measure these analytes in mutant mice models which confirmed the characterizations of these species in vivo. Chapter Four represents the culmination of a decade long project to investigate and characterize the toxicity of the copper ionophore thiomaltol (Htma) against human melanoma. While many strategies have been developed to target melanoma cancer, recent discoveries of copper regulation being correlated to highly upregulated signaling pathways like MAPK have resulted in many ionophore-related strategies to target melanoma in a copper-dependent fashion. Htma/Cu treatment appears to cause copper hyperaccumulation within lysosomes within a few hours with simultaneous proteasome inhibition leading to an apoptotic death response within 24 hours. Altogether, this work encourages further use of the LCMS strategy described to study biological sulfur metabolites in other models as well as the examination of copper trafficking protein networks under stress from copper ionophores.



Hydrogen sulfide. Copper.