Kinetic and cellular characterization of novel inhibitors of S-nitrosoglutathione reductase.
S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of S-nitrosothiols (SNOs) in vivo. Knock-out studies in mice have shown that GSNOR regulates the smooth muscle tone in airways and the function of beta-adrenergic receptors in lungs and heart. GSNOR has emerged as a target for the development of therapeutic approaches for treating lung and cardiovascular diseases. We report three compounds that exclude GSNOR substrate, S-nitrosoglutathione (GSNO) from its binding site in GSNOR and cause an accumulation of SNOs inside the cells. The new inhibitors selectively inhibit GSNOR among the alcohol dehydrogenases. Using the inhibitors, we demonstrate that GSNOR limits nitric oxide-mediated suppression of NF-kappaB and activation of soluble guanylyl cyclase. Our findings reveal GSNOR inhibitors to be novel tools for regulating nitric oxide bioactivity and assessing the role of SNOs in vivo.
Sanghani
Paresh C
PC
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Davis
Wilhelmina I
WI
Fears
Sharry L
SL
Green
Scheri-Lyn
SL
Zhai
Lanmin
L
Tang
Yaoping
Y
Martin
Emil
E
Bryan
Nathan S
NS
Sanghani
Sonal P
SP
D000426:Alcohol Dehydrogenase; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008171:Lung Diseases / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D026422:S-Nitrosoglutathione / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D005980:Glutathione Reductase; D006162:Guanylate Cyclase