S. Bruce King
PhD., Cornell University
Post Doctoral, The Scripps Research Institute,
K. Barry Sharpless
Henry Dreyfus Teacher Scholar Award (1999-2004)
Z. Smith Reynolds Foundation Fellow (2001-2004)
Office: Salem 15B
Phone: (336) 758-5774
Our research program focuses on understanding the redox chemistry responsible for biological activity. To achieve these research goals, we use a combination of synthetic and physical organic chemistry, biochemistry and biophysics to elucidate the identity, reactivity and effects of biological redox species. Much of our work centers 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 and to understand biological pathways of HNO formation. These studies support the exciting emerging use of HNO-donors as therapeutic agents for congestive heart failure.
Directly related to this work has been the examination of dietary nitrate, found in numerous green leafy vegetables, as a source of nitric oxide. This work, in collaboration with Dany Kim-Shapiro (WFU Physics) and the Translational Science Center (TSC) examines the role nitrate and nitrite play in normal physiology and the biochemical pathways that convert these nitrogen species between different redox states. 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. Other projects (with Leslie Poole, WFU Biochemistry and Cristina Furdui, WFU Molecular Medicine) 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. As such, the bio-organic chemistry of sulfur and sulfur-containing compounds plays a prominent role in our laboratory’s work.
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.
Recent Selected Publications (Since 2010)
Miller, G.D.; Marsh, A.P.; Dove, R.W.; Beavers, D.; Presley, T.; Helms, C.; Bechtold, E.; King, S.B.; Kim-Shapiro, D.B. “Plasma Nitrate and Nitrite are Increased by a High-Nitrate Supplement but not by High-Nitrate Foods in Older Adults,” Nutr. Res. 2012, 32, 160-168.
Flores-Santana, W.; Moody, T.; Chen, W.; Gorczynski, M.J.; Shoman, M.E.; Velazquez, C.; Thetford, A.; Mitchell, J. B.; Cherukuri, M. K.; King, S. B.; Wink, D. A. “Nitroxide Derivatives of Non-Steroidal Anti-Inflammatory Drugs Exert Anti-Inflammatory and Superoxide Dismutase Scavenging Properties in A459 Cells,” Brit. J. Pharmacol. 2012, 165, 1058-1067.
Ding, W.; Li, Z.; Shen, X.; Martin, J.; King, S.B.; Sivakumaran, V.; Paolocci, N.; Gao, W. D.; “Reversal of Isoflurane-Induced Depression of Myocardial Contraction by Nitroxyl via Myofilament Sensitization to Ca+2,” Pharmacology and Experimental Therapeutics 2011, 339, 825-831.
Bates, D. J. P.; Smiterman, P. K.; Townsend, A. J.; King, S.B.; Morrow, C. S. “Nitroalkene Fatty Acids Mediate Activation of Nrf2/ARE-Dependent and PPARg-Dependent Transcription by Distinct Signaling Pathways and with Significantly Different Potencies,” Biochemistry 2011, 50, 7765-7773.
Reisz, J. A.; Zink, C. N.; King, S. B. “Rapid and Selective Nitroxyl (HNO) Trapping by Phosphines: Kinetics and New Aqueous Ligations for HNO Detection and Quantitation,” J. Am. Chem. Soc. 2011, 133, 11675-11685.
Wani, R.; Qian, J.; Yin, L.M.; Bechtold, E.; King, S. B.; Poole, L. B.; Paek, E.; Tsang, A. W.; Furdui, C. M. “Isoform-specific Regulation of Akt by PDGF-induced Reactive Oxygen Species,” Proc. Natl Acad. Sci., USA, 2011, 108, 10550-10555.
Qian, J.; Klomsiri, C.; Wright, M.W.; King, S. B.; Tsang, A. W.; Poole, L. B.; Furdui, C. M.; “Simple Synthesis of 1, 3-cyclopentanedione derived probes for labeling sulfenic acid proteins,” Chemical Commun. 2011, 47, 9203-9205.
DuMond, J. F.; King, S. B. “The Chemistry of Nitroxyl-Releasing Compounds,” Antioxidants and Redox Signaling, 2011, 14, 1637-1648.
Huang, Z.; Velazquez, C. A.; Abdellatif, K. R. A.; Chowdhury, M. A.; Reisz, J. A.; DuMond, J. F.; King, S. B.; Knaus, E. E. “Ethanesulfohydroxamic Acid Ester Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Synthesis, Nitric Oxide and Nitroxyl Release, Cyclooxygenase Inhibition, Anti-Inflammatory and Ulcerogenicity Index Studies,” J. Med. Chem. 2011, 54, 1356-1364.
Shoman, M. E.; Dumond, J.F.; Isbell, T. S.; Crawford, J. H.; Brandon A.; Honovar, J.; Vitturi, D. A.; White, C. R.; Patel, R. P.; King, S. B. “Acyloxy Nitroso Compounds as Nitroxyl (HNO) Donors: Kinetics, Reactions with Thiols and Vasodilation Properties,” J. Med. Chem. 2011, 54, 1059-1070.
Presley, T. D.; Morgan, A. R.; Bechtold, E.; Clodfelter, W.; Dove, R. W.; Jennings, J. M.; Kraft, R. A.; King, S. B.; Laurienti, P. J.; Rejeski, W. J.; Burdette, J. H.; Kim-Shapiro, D. B.; Miller, G. D. “Acute Effect of High Nitrtate Diet on Brain Perfusion in Older Adults,” Nitric Oxide, 2011, 24, 34-42.
Klomsiri, C.; Nelson, K. J.; Bechtold, E.; Soito, L.; Johnson, L. C.; Lowther, W. T.; Ryu, S-E.; King, S. B.; Furdui, C. M.; Poole, L. B. “Use of Dimedone-Based Chemical Probes for Sulfenic Acid Detection: Evaluation of Conditions Affecting Probe Incorporation into Redox-Sensitive Proteins,” Methods in Enzymology 2010, 473, 77-94.
Reisz, J. A.; Bechtold, E.; King, S. B. “Oxidative Heme Protein-Mediated Nitroxyl (HNO) Generation,” Dalton Trans., 2010, 39, 5203-5212.
Bechtold, E.; Reisz, J. A.; Klomsiri, C.; Allen W. Tsang, A. W.;Marcus W. Wright, M. W.; Poole, L. B.; Furdui, C. M.; King, S. B. “Water-Soluble Triarylphosphines as Biomarkers for Protein S-Nitrosation,” ACS Chemical Biology, 2010, 5, 405-414.