Chemical Biology of Nitroxyl (HNO)

Wink, David

Abstract

the chemical biology of HNO, is to determine the pharmacological and possible endogenous production of this species in vivo. One of the challenges is to determine the role that HNO may have in the biochemistry of nitric oxide synthase (NOS). In addition, we have found that NH2OH may be an important precursor to HNO under oxidative conditions. This indicates that hydroxyamic acids such as chemotherapeutic drugs hydroxyurea and SAHA may mediate some effects through HNO. Here we have investigated a variety of HNO donors and method of generation in vivo. We have currently discover a specific marker for HNO and found that it can be detected in cells. Furhtermore, we have been able to determine protemic and genomic signature that differ from HNO and NO. These finding furhter support our hypothesis that these species have mutaully exclusive biology.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIABC011190-05
• Application #: 8763389
• Support Year: 5
• Fiscal Year: 2013
• Total Cost: $67,074

Institution

• Name: National Cancer Institute Division of Basic Sciences

Publications

Gao, Wei Dong; Murray, Christopher I; Tian, Ye et al. (2012) Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function. Circ Res 111:1002-11

Fukuto, Jon M; Carrington, Samantha J; Tantillo, Dean J et al. (2012) Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species. Chem Res Toxicol 25:769-93

Flores-Santana, Wilmarie; Salmon, Debra J; Donzelli, Sonia et al. (2011) The specificity of nitroxyl chemistry is unique among nitrogen oxides in biological systems. Antioxid Redox Signal 14:1659-74

Schoenfeld, Michael P; Ansari, Rafat R; Zakrajsek, June F et al. (2011) Hydrogen therapy may reduce the risks related to radiation-induced oxidative stress in space flight. Med Hypotheses 76:117-8

Tocchetti, Carlo G; Stanley, Brian A; Murray, Christopher I et al. (2011) Playing with cardiac ""redox switches"": the ""HNO way"" to modulate cardiac function. Antioxid Redox Signal 14:1687-98

Andrei, Daniela; Salmon, Debra J; Donzelli, Sonia et al. (2010) Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class. J Am Chem Soc 132:16526-32

Switzer, Christopher H; Flores-Santana, Wilmarie; Mancardi, Daniele et al. (2009) The emergence of nitroxyl (HNO) as a pharmacological agent. Biochim Biophys Acta 1787:835-40

Paolocci, Nazareno; Wink, David A (2009) The shy Angeli and his elusive creature: the HNO route to vasodilation. Am J Physiol Heart Circ Physiol 296:H1217-20

Samuni, Yuval; Flores-Santana, Wilmarie; Krishna, Murali C et al. (2009) The inhibitors of histone deacetylase suberoylanilide hydroxamate and trichostatin A release nitric oxide upon oxidation. Free Radic Biol Med 47:419-23

Donzelli, Sonia; Espey, Michael Graham; Flores-Santana, Wilmarie et al. (2008) Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine. Free Radic Biol Med 45:578-84