Description of Research
Our research program focuses on understanding the redox chemistry responsible for biological activities. To achieve these research goals, our group uses a combination of synthetic and physical organic chemistry, biochemistry and biophysics to elucidate the identity, reactivity and effects of various biological redox species. In the past, much of our work centered on nitric oxide (NO) and the role it performs in biological systems. Nitric oxide directly participates in the control of blood flow and pressure, neurotransmission, and the immune response and the regulation of NO levels represents a therapeutic strategy for disease states characterized by abnormal NO production. Most recently our laboratory has focused on NO redox forms including nitroxyl (HNO) and the common inorganic salts of nitrite and nitrate (NO2- and NO3-). Nitroxyl (HNO) remains a difficult molecule to study as it must be generated from precursors and its inherent reactivity makes identification relatively difficult. Specifically, we pursue the synthesis and evaluation of new organic compounds as HNO donors and the development of new organic-based methods of detection. As part of this study, we are attempting to better define the reactions of HNO with biological molecules, especially thiols and thiol-containing proteins. These studies support the exciting emerging use of HNO-donors as therapeutic agents for congestive heart failure. In addition to HNO, other projects (with Leslie Poole, WFU Biochemistry) examine the role of hydrogen peroxide as a redox-based signaling agent. These experiments define the sites, mechanisms and consequences of protein thiol oxidation (to sulfenic, sulfinic, or sulfonic acids, or disulfides) through the synthesis of unique protein labels followed by mass spectroscopic studies of reactions with proteins and whole cells. The NO, HNO and hydrogen peroxide projects merge with other studies designed to develop new methods and probes for other thiol-based oxidative modifications including sulfinamides, S-nitrosothiols and sulfenyl chlorides.
Projects in collaboration with Dany Kim-Shapiro, WFU Physics and the newly formed Translational Science Center (TSC) examine the role nitrate and nitrite play in normal physiology. Nitrate is found as a dietary nutrient and can act as a source of NO via the intermediacy of nitrite. Current studies attempt to define optimal nitrate-containing diets, mechanisms of nitrate conversion to nitrite and NO and the development of organic molecules as sources of nitrate or nitrite. The fundamental reactions of these simple compounds with biological compounds (especially proteins) also constitute a major research thrust. Finally, Dr. King directs the Synthetic Core Laboratory of the WFU Comprehensive Cancer Center and our group participates in collaborative projects that pair our synthetic abilities with numerous biological and computational scientists to development new molecules for cancer treatment. Hopefully, these fundamental studies in chemical biology will provide a better idea of the process of redox chemistry in biology and carcinogenesis. --READ MORE--