S-Nitrosoglutathione

Last updated
S-Nitrosoglutathione
Nitrosoglutathione.svg
Names
IUPAC name
L-γ-Glutamyl-S-nitroso-L-cysteinylglycine
Systematic IUPAC name
(2S)-2-Amino-5-({(2R)-1-[(carboxymethyl)amino]-3-(nitrososulfanyl)-1-oxopropan-2-yl}amino)-5-oxopentanoic acid
Other names
Glutathione thionitrite; S-Nitroso-L-glutathione; SNOG; GSNO
Identifiers
3D model (JSmol)
3566211
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.165.055 OOjs UI icon edit-ltr-progressive.svg
MeSH S-Nitrosoglutathione
PubChem CID
RTECS number
  • MC0558000
UNII
  • InChI=1S/C10H16N4O7S/c11-5(10(19)20)1-2-7(15)13-6(4-22-14-21)9(18)12-3-8(16)17/h5-6H,1-4,11H2,(H,12,18)(H,13,15)(H,16,17)(H,19,20)/t5-,6-/m0/s1 Yes check.svgY
    Key: HYHSBSXUHZOYLX-WDSKDSINSA-N Yes check.svgY
  • C(CC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)[C@@H](C(=O)O)N
Properties
C10H16N4O7S
Molar mass 336.32 g·mol−1
log P −2.116
Acidity (pKa)2.212
Basicity (pKb)11.785
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

S-Nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol (SNO) that plays a critical role in nitric oxide (NO) signaling and is a source of bioavailable NO. NO coexists in cells with SNOs that serve as endogenous NO carriers and donors. SNOs spontaneously release NO at different rates and can be powerful terminators of free radical chain propagation reactions, by reacting directly with ROO• radicals, yielding nitro derivatives as end products. [1] NO is generated intracellularly by the nitric oxide synthase (NOS) family of enzymes: nNOS, eNOS and iNOS while the in vivo source of many of the SNOs is unknown. In oxygenated buffers, however, formation of SNOs is due to oxidation of NO to dinitrogen trioxide (N2O3). [2] Some evidence suggests that both exogenous NO and endogenously derived NO from nitric oxide synthases can react with glutathione to form GSNO.

Contents

GSNOR

The enzyme GSNO reductase (GSNOR) reduces S-nitrosoglutathione (GSNO) to an unstable intermediate, S-hydroxylaminoglutathione, which then rearranges to form glutathione sulfonamide, or in the presence of GSH, forms oxidized glutathione (GSSG) and hydroxylamine. [3] [4] [5] Through this catabolic process, GSNOR regulates the cellular concentrations of GSNO and plays a central role in regulating the levels of endogenous S-nitrosothiols and controlling protein S-nitrosylation-based signaling.

The chemical synthesis of GSNO GSNO figure.png
The chemical synthesis of GSNO

The generation of GSNO can serve as a stable and mobile NO pool which can effectively transduce NO signaling. [6] [7] Unlike other low molecular weight messengers that bind to and activate target cellular receptors, NO signaling is mediated by a coordinating complex between NO and transition metals or target cellular proteins, often via S-nitrosylation of cysteine residues. [8] [9] [10] Studies suggest that NO metabolism has a significant role in human cardiovascular and respiratory diseases as well as in immune tolerance during organ transplantation. [11] [12] [13] [14]

GSNO in Health and Disease

GSNO and NO concentrations regulate respiratory function by modulating airway tone and pro- and anti-inflammatory responses in the respiratory tract. [14] [15] Because NO is a labile gas and endogenous levels are difficult to manipulate, it has been proposed that exogenous GSNO could be used to regulate circulating levels of NO and NO-derived species, and GSNO could have value in patients with pulmonary diseases such as cystic fibrosis. Consistent with this therapeutic goal, a recent study showed that acute treatment with aerosolized GSNO was well tolerated by cystic fibrosis patients. [14]

SNOs in the hepatic mitochondria appear to influence proper functioning of the liver. Mitochondrial SNO-proteins inhibit Complex I of the electron transport chain; modulate mitochondrial reactive oxygen species (ROS) production; influence calcium-dependent opening of the mitochondrial permeability transition pore; promote selective importation of mitochondrial proteins; and stimulate mitochondrial fission. Altered redox balance plays a crucial role in the pathogenesis of liver diseases including steatosis, steatohepatitis, and fibrosis. The ease of reversibility and the interplay of S-nitrosating and denitrosating enzymatic reactions support the hypothesis that SNOs regulate the mitochondrion through redox mechanisms. [16]

In a study evaluating the effects on ursodeoxycholic acid (UDCA) on bile flow and cirrhosis, NO was found in bile as SNOs, primarily GSNO. UDCA-stimulated biliary NO secretion was abolished by the inhibition of iNOS with L-NAME in isolated perfused livers and also in rat livers depleted of GSH with buthionine sulfoximine. Moreover, the biliary secretion of NO species was significantly diminished in UDCA-infused transport mutant [ATP–binding cassette C2/multidrug resistance–associated protein 2–deficient] rats, and this finding was consistent with the involvement of the glutathione carrier ABCC2/Mrp2 in the canalicular transport of GSNO. It was particularly noteworthy that in cultured normal rat cholangiocytes, GSNO activated protein kinase B, protected against apoptosis, and enhanced UDCA-induced ATP release to the medium. [17] Finally, they demonstrated that retrograde GSNO infusion into the common bile duct increased bile flow and biliary bicarbonate secretion. The study concluded that UDCA-induced biliary secretion of GSNO contributed to stimulating ductal secretion of bile.

Neuromodulator

GSNO, along with glutathione and oxidized glutathione (GSSG), have been found to bind to the glutamate recognition site of the NMDA and AMPA receptors (via their γ-glutamyl moieties), and may be endogenous neuromodulators. [18] [19] At millimolar concentrations, they may also modulate the redox state of the NMDA receptor complex. [19]

Related Research Articles

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">Primary biliary cholangitis</span> Autoimmune disease of the liver

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

Agmatine, also known as 4-aminobutyl-guanidine, was discovered in 1910 by Albrecht Kossel. It is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, ion channels, nitric oxide (NO) synthesis and polyamine metabolism and this provides bases for further research into potential applications.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

<span class="mw-page-title-main">Ursodeoxycholic acid</span> Medication and metabolite of cholesterol

Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived. In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts.

<span class="mw-page-title-main">Glutathione disulfide</span> Chemical compound

Glutathione disulfide (GSSG) is a disulfide derived from two glutathione molecules.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:

<span class="mw-page-title-main">Bile acid</span> Steroid acid found predominantly in the bile of mammals and other vertebrates

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<span class="mw-page-title-main">PDZ domain</span>

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<span class="mw-page-title-main">NFE2L2</span> Human protein and coding gene

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Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene.

<span class="mw-page-title-main">7-Nitroindazole</span> Chemical compound

7-Nitroindazole, or 7-NI, is a heterocyclic small molecule containing an indazole ring that has been nitrated at the 7 position. Nitroindazole acts as a selective inhibitor for neuronal nitric oxide synthase, a hemoprotein enzyme that, in neuronal tissue, converts arginine to citrulline and nitric oxide (NO). Nitric oxide can diffuse through the plasma membrane into neighbouring cells, allowing cell signalling, so nitroindazole indirectly inhibits this signalling process. Other inhibitors exist such as 3-bromo-7-nitroindazole, which is more potent but less specific, or NPA (N-propyl-L-arginine), which acts on a different site.

<i>S</i>-Nitrosothiol Organic compounds or groups of the form –S–N=O

In organic chemistry, S-nitrosothiols, also known as thionitrites, are organic compounds or functional groups containing a nitroso group attached to the sulfur atom of a thiol. S-Nitrosothiols have the general formula R−S−N=O, where R denotes an organic group. Originally suggested by Ignarro to serve as intermediates in the action of organic nitrates, endogenous S-nitrosothiols were discovered by Stamler and colleagues (S-nitrosoalbumin in plasma and S-nitrosoglutathione in airway lining fluid) and shown to represent a main source of NO bioactivity in vivo. More recently, S-nitrosothiols have been implicated as primary mediators of protein S-nitrosylation, the oxidative modification of cysteine thiol that provides ubiquitous regulation of protein function.

In biochemistry, S-nitrosylation is the covalent attachment of a nitric oxide group to a cysteine thiol within a protein to form an S-nitrosothiol (SNO). S-Nitrosylation has diverse regulatory roles in bacteria, yeast and plants and in all mammalian cells. It thus operates as a fundamental mechanism for cellular signaling across phylogeny and accounts for the large part of NO bioactivity.

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Ted M. Dawson is an American neurologist and neuroscientist. He is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and Director of the Institute for Cell Engineering at Johns Hopkins University School of Medicine. He has joint appointments in the Department of Neurology, Neuroscience and Department of Pharmacology and Molecular Sciences.

<span class="mw-page-title-main">Jonathan Stamler</span> English-American physician and biochemist

Jonathan Solomon Stamler is an English-born American physician and scientist. He is known for his discovery of protein S-nitrosylation, the addition of a nitric oxide (NO) group to cysteine residues in proteins, as a ubiquitous cellular signal to regulate enzymatic activity and other key protein functions in bacteria, plants and animals, and particularly in transporting NO on cysteines in hemoglobin as the third gas in the respiratory cycle.

References

  1. ↑ de Oliveira CP, de Lima VM, Simplicio FI, Soriano FG, de Mello ES, de Souza HP, Alves VA, Laurindo FR, Carrilho FJ, de Oliveira MG (April 2008). "Prevention and reversion of nonalcoholic steatohepatitis in OB/OB mice by S-nitroso-N-acetylcysteine treatment". J Am Coll Nutr. 27 (2): 299–305. doi:10.1080/07315724.2008.10719703. PMID   18689562. S2CID   29904719.
  2. ↑ Giustarini D, Milzani A, Dalle-Donne I, Rossi R (May 2007). "Detection of S-nitrosothiols in biological fluids: a comparison among the most widely applied methodologies". J. Chromatogr. B. 851 (1–2): 124–39. doi:10.1016/j.jchromb.2006.09.031. PMID   17035104.
  3. ↑ Hedberg JJ, Griffiths WJ, Nilsson SJ, Höög JO (March 2003). "Reduction of S-nitrosoglutathione by human alcohol dehydrogenase 3 is an irreversible reaction as analysed by electrospray mass spectrometry". Eur. J. Biochem. 270 (6): 1249–56. doi:10.1046/j.1432-1033.2003.03486.x. PMID   12631283.
  4. ↑ Jensen DE, Belka GK, Du Bois GC (April 1998). "S-Nitrosoglutathione is a substrate for rat alcohol dehydrogenase class III isoenzyme". Biochem. J. 331 (2): 659–68. doi:10.1042/bj3310659. PMC   1219401 . PMID   9531510.
  5. ↑ Staab CA, Alander J, Morgenstern R, Grafström RC, Höög JO (March 2009). "The Janus face of alcohol dehydrogenase 3". Chem. Biol. Interact. 178 (1–3): 29–35. doi:10.1016/j.cbi.2008.10.050. PMID   19038239.
  6. ↑ Dijkers PF, O'Farrell PH (September 2009). "Dissection of a hypoxia-induced, nitric oxide-mediated signaling cascade". Mol. Biol. Cell. 20 (18): 4083–90. doi:10.1091/mbc.E09-05-0362. PMC   2743626 . PMID   19625446.
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  8. ↑ Derakhshan B, Hao G, Gross SS (July 2007). "Balancing reactivity against selectivity: the evolution of protein S-nitrosylation as an effector of cell signaling by nitric oxide". Cardiovasc. Res. 75 (2): 210–9. doi:10.1016/j.cardiores.2007.04.023. PMC   1994943 . PMID   17524376.
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  10. ↑ Kone BC (August 2006). "S-Nitrosylation: Targets, Controls and Outcomes". Current Genomics. 7 (5): 301–10. doi:10.2174/138920206778604340.
  11. ↑ Casey DP, Beck DT, Braith RW (December 2007). "Systemic plasma levels of nitrite/nitrate (NOx) reflect brachial flow-mediated dilation responses in young men and women". Clin. Exp. Pharmacol. Physiol. 34 (12): 1291–3. doi:10.1111/j.1440-1681.2007.04715.x. PMID   17973870. S2CID   32999331.
  12. ↑ Ganz P, Vita JA (October 2003). "Testing endothelial vasomotor function: nitric oxide, a multipotent molecule". Circulation. 108 (17): 2049–53. doi:10.1161/01.CIR.0000089507.19675.F9. PMID   14581383.
  13. ↑ Que LG, Liu L, Yan Y, Whitehead GS, Gavett SH, Schwartz DA, Stamler JS (June 2005). "Protection from experimental asthma by an endogenous bronchodilator". Science. 308 (5728): 1618–21. Bibcode:2005Sci...308.1618Q. doi:10.1126/science.1108228. PMC   2128762 . PMID   15919956..
  14. 1 2 3 Snyder AH, McPherson ME, Hunt JF, Johnson M, Stamler JS, Gaston B (April 2002). "Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis" (PDF). Am. J. Respir. Crit. Care Med. 165 (7): 922–6. doi:10.1164/ajrccm.165.7.2105032. hdl: 1808/16125 . PMID   11934715.
  15. ↑ Gaston B, Reilly J, Drazen JM, Fackler J, Ramdev P, Arnelle D, Mullins ME, Sugarbaker DJ, Chee C, Singel DJ (December 1993). "Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways". Proc. Natl. Acad. Sci. U.S.A. 90 (23): 10957–61. Bibcode:1993PNAS...9010957G. doi: 10.1073/pnas.90.23.10957 . PMC   47900 . PMID   8248198.
  16. ↑ Piantadosi CA (March 2011). "Regulation of mitochondrial processes by protein S-nitrosylation". Biochim Biophys Acta. 1820 (6): 712–21. doi:10.1016/j.bbagen.2011.03.008. PMC   3162082 . PMID   21397666.
  17. ↑ Rodríguez-Ortigosa CM, Banales JM, Olivas I, Uriarte I, Marín JJ, Corrales FJ, Medina JF, Prieto J (August 2010). "Biliary secretion of S-nitrosoglutathione is involved in the hypercholeresis induced by ursodeoxycholic acid in the normal rat". Hepatology. 52 (2): 667–77. doi:10.1002/hep.23709. PMID   20683964.
  18. ↑ Steullet, P.; Neijt, H.C.; Cuénod, M.; Do, K.Q. (2006). "Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia". Neuroscience. 137 (3): 807–819. doi:10.1016/j.neuroscience.2005.10.014. ISSN   0306-4522. PMID   16330153. S2CID   1417873.
  19. 1 2 Varga, V.; Jenei, Zs.; Janáky, R.; Saransaari, P.; Oja, S. S. (1997). "Glutathione is an endogenous ligand of rat brain N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors". Neurochemical Research. 22 (9): 1165–1171. doi:10.1023/A:1027377605054. ISSN   0364-3190. PMID   9251108. S2CID   24024090.

for the synthesis of S-Nitrosoglutathione see Hart, T.W., 1985. Some observations concerning the S-nitroso and S-phenylsulphonyl derivatives of L-cysteine and glutathione. Tetrahedron Letters, 26(16), pp.2013-2016.