Seleno Compounds and Glutathione Peroxidase Catalyzed Decomposition ofS-Nitrosothiols

Hou, Yongchun; Guo, Zhengmao; Li, Jun; Wang, Peng George

doi:10.1006/bbrc.1996.1620

Cited by 140 publications

(77 citation statements)

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“…The importance of regulating GSNO concentration is evident given its functions as a carrier of nitric oxide, which may include roles in microbial host defense, smooth muscle relaxation, bronchiolar dilation, and transcription factor regulation (22)(23)(24). Although several enzymes have been reported to degrade GSNO (25)(26)(27), only GSH-dependent FDH has been shown to regulate endogenous levels of GSNO (15) by use of a nicotinamide co-factor. This enzyme is unusual in that it utilizes NADH for reduction rather than the usual in vivo reductant, NADPH.…”

Section: Resultsmentioning

confidence: 99%

Human Carbonyl Reductase 1 Is an S-Nitrosoglutathione Reductase

Bateman

Rauh

Tavshanjian

et al. 2008

Journal of Biological Chemistry

122

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Human carbonyl reductase 1 (hCBR1) is an NADPH-dependent short chain dehydrogenase/reductase with broad substrate specificity and is thought to be responsible for the in vivo reduction of quinones, prostaglandins, and other carbonyl-containing compounds including xenobiotics. In addition, hCBR1 possesses a glutathione binding site that allows for increased affinity toward GSH-conjugated molecules. It has been suggested that the GSH-binding site is near the active site; however, no structures with GSH or GSH conjugates have been reported. We have solved the x-ray crystal structures of hCBR1 and a substrate mimic in complex with GSH and the catalytically inert GSH conjugate hydroxymethylglutathione (HMGSH). The structures reveal the GSH-binding site and provide insight into the affinity determinants for GSH-conjugated substrates. We further demonstrate that the structural isostere of HMGSH, S-nitrosoglutathione, is an ideal hCBR1 substrate (K m ‫؍‬ 30 M, k cat ‫؍‬ 450 min ؊1 ) with kinetic constants comparable with the best known hCBR1 substrates. Furthermore, we demonstrate that hCBR1 dependent GSNO reduction occurs in A549 lung adenocarcinoma cell lysates and suggest that hCBR1 may be involved in regulation of tissue levels of GSNO.Human carbonyl reductase 1 (hCBR1), 3 an NADPH-dependent enzyme belonging to the short chain dehydrogenase/reductase family, has been shown to be involved in the metabolism of structurally diverse carbonyl-containing substances. This is in contrast to other members of the short chain dehydrogenase/ reductase family, such as 11␤-hydroxysteroid dehydrogenases 1 and 2 that interconvert cortisone and cortisol, and the 17␤-hydroxysteroid dehydrogenases, which have well defined androgen and estrogen substrates. Previously reported substrates of hCBR1 include prostaglandins and xenobiotics such as the anti-cancer anthracyclin doxorubicin and the vitamin K2 precursor menadione (1). More recently, hCBR1 has been linked to the detoxification of reactive aldehydes such as 4-oxonon-2-enal and its GSH conjugate that are believed to play a central role in oxidative stress-related neurodegenerative disorders including Alzheimer and Parkinson diseases (2). Although extensive biological investigations of hCBR1, including RNA interference, pharmacology, and crystallography of human hCBR1 in complex with substrate mimics, have been carried out (3), the endogenous physiological substrate(s) of this enzyme remain to be defined. One well accepted aspect of hCBR1 substrate recognition is the presence of a GSH-binding pocket predicted to be in close proximity to the catalytic site. GSH conjugates of otherwise poorly recognized substrates such as prostaglandin A1 are reduced by hCBR1 (4), supporting this hypothesis. To identify additional physiological substrates of hCBR1, we initiated a structural biology effort to analyze the GSH-binding site of hCBR1, hypothesizing that cellular GSH adducts might serve as particularly good hCBR1 substrates.We solved the x-ray co-crystal structure of hCBR1 in complex with G...

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Section: Resultsmentioning

confidence: 99%

Human Carbonyl Reductase 1 Is an S-Nitrosoglutathione Reductase

Bateman

Rauh

Tavshanjian

et al. 2008

Journal of Biological Chemistry

122

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“…The mechanism of SNO formation in vivo is obscure (Hogg, 2002) but, once generated, the SNO can be passed between thiols by transnitrosation, with the formation and stability of the SNO determined by protein sequence motifs that surround the modified cysteine residue (Benhar et al, 2009;Doulias et al, 2010;Hou et al, 1996;Marino and Gladyshev, 2010;Nikitovic and Holmgren, 1996). In addition, an initial SNO on a protein can be modified into other thiol-based groups, such as disulphide, sulphenic acid or into a glutathionylated protein (Nikitovic and Holmgren, 1996;Stamler et al, 1992).…”

Section: Post-translational Protein Modification By H 2 O 2 and Nomentioning

confidence: 99%

Mitochondrial redox signalling at a glance

Collins

Chouchani

James

et al. 2012

Journal of Cell Science

230

152

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“…SNP contains an NO group in the oxidation state NO ϩ and can act as a nitrosating agent at neutral pH values (24), whereas GSNO and SNAP are S-nitrosothiols often used by researchers as NO donors due to their spontaneous decomposition to NO (17,18). The effect on the norB strain was very marked; concentrations of SNP, GSNO, and SNAP which allowed rapid growth of the wild-type strain severely attenuated growth of N. meningitidis MA2.…”

Section: Fig 1 Effect Of Nitrite On Growth Of N Meningitidis Growmentioning

confidence: 99%

Nitric Oxide Metabolism in Neisseria meningitidis

et al. 2002

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Neisseria meningitidis, the causative agent of meningococcal disease in humans, is likely to be exposed to nitrosative stress during natural colonization and disease. The genome of N. meningitidis includes the genes aniA and norB, predicted to encode nitrite reductase and nitric oxide (NO) reductase, respectively. These gene products should allow the bacterium to denitrify nitrite to nitrous oxide. We show that N. meningitidis can support growth microaerobically by the denitrification of nitrite via NO and that norB is required for anaerobic growth with nitrite. NorB and, to a lesser extent, the cycP gene product cytochrome c are able to counteract toxicity due to exogenously added NO. Expression of these genes by N. meningitidis during colonization and disease may confer protection against exogenous or endogenous nitrosative stress.

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Seleno Compounds and Glutathione Peroxidase Catalyzed Decomposition ofS-Nitrosothiols

Cited by 140 publications

References 0 publications

Human Carbonyl Reductase 1 Is an S-Nitrosoglutathione Reductase

Human Carbonyl Reductase 1 Is an S-Nitrosoglutathione Reductase

Mitochondrial redox signalling at a glance

Nitric Oxide Metabolism in Neisseria meningitidis

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