The previous funding period examined the chemical basis for the interactions between thiols, peroxynitrite and nitric oxide. It has become apparent that S-nitrosothiols (RSNO), biological metabolites of nitric oxide and thiols, play divers roles in potentiating and modulating the effects of nitric oxide. These include an anti-platelet function and vessel relaxation in terms of extracellular effects, and is also the intracellular modulation of enzyme activities and signaling pathways. Very little is known about the metabolism of RSNO. It is often assumed that these compounds spontaneously liberate nitric oxide and these compounds are commercially available as nitric oxide donors. However, this assumption is in error and RSNO are stable compounds that require an additional agent to promote decomposition. This application proposes to investigate the molecular interactions of S-nitrosothiols with biological targets to understand more fully their role in biological systems. This will be done by addressing three hypothesis with associated specific aims: 1) The observations that protein thiols are the major intracellular targets of RSNO has led us to promote that the modification of protein thiol residues by RSNO is controlled by the local environment of the protein thiol.
This specific aim will ask the crucial questions of what makes a particular thiol susceptible to control by RSNO: II) Our observations that heme proteins can directly reduce S-nitrosothiols have led us to propose that ferrous heme groups are a major site of RSNO metabolism. In this specific aim, we will explore the role played by heme moieties in the control of nitric oxide release from RSNO. III) Our observations concerning the metabolism of RSNO by endothelial cells has led us to propose that cells contain an active metabolic pathway for the metabolism of RSNO. These studiers will investigate the mechanism of RSNO metabolism by various cell types. The biochemistry of RSNO has been linked to asthma, inflammation, hypertension, apoptosis and atherosclerosis. It is envisioned that this study will yield new insights into the roles played by these important compounds and aid pharmacological development of new and more selectively potent S- nitrosothiols.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM055792-06A1
Application #
6436383
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Ikeda, Richard A
Project Start
1997-04-01
Project End
2005-11-30
Budget Start
2001-12-10
Budget End
2002-11-30
Support Year
6
Fiscal Year
2002
Total Cost
$263,900
Indirect Cost
Name
Medical College of Wisconsin
Department
Biophysics
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Keszler, Agnes; Diers, Anne R; Ding, Zhen et al. (2017) Thiolate-based dinitrosyl iron complexes: Decomposition and detection and differentiation from S-nitrosothiols. Nitric Oxide 65:1-9
Chang, Ching-Fang; Diers, Anne R; Hogg, Neil (2015) Cancer cell metabolism and the modulating effects of nitric oxide. Free Radic Biol Med 79:324-36
Diers, Anne R; Broniowska, Katarzyna A; Chang, Ching-Fang et al. (2014) S-Nitrosation of monocarboxylate transporter 1: inhibition of pyruvate-fueled respiration and proliferation of breast cancer cells. Free Radic Biol Med 69:229-38
Diers, Anne R; Keszler, Agnes; Hogg, Neil (2014) Detection of S-nitrosothiols. Biochim Biophys Acta 1840:892-900
Diers, Anne R; Broniowska, Katarzyna A; Hogg, Neil (2013) Nitrosative stress and redox-cycling agents synergize to cause mitochondrial dysfunction and cell death in endothelial cells. Redox Biol 1:1-7
Broniowska, Katarzyna A; Diers, Anne R; Corbett, John A et al. (2013) Effect of nitric oxide on naphthoquinone toxicity in endothelial cells: role of bioenergetic dysfunction and poly (ADP-ribose) polymerase activation. Biochemistry 52:4364-72
Broniowska, Katarzyna A; Diers, Anne R; Hogg, Neil (2013) S-nitrosoglutathione. Biochim Biophys Acta 1830:3173-81
Broniowska, Katarzyna A; Keszler, Agnes; Basu, Swati et al. (2012) Cytochrome c-mediated formation of S-nitrosothiol in cells. Biochem J 442:191-7
Diers, Anne R; Broniowska, Katarzyna A; Chang, Ching-Fang et al. (2012) Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem J 444:561-71
Diers, Anne R; Broniowska, Katarzyna A; Darley-Usmar, Victor M et al. (2011) Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells. Am J Physiol Heart Circ Physiol 301:H803-12

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