S-Nitrosoglutathione
Encyclopedia
S-Nitrosoglutathione 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. 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). Some evidence suggests that both exogenous NO and endogenously derived NO from nitric oxide synthases can react with glutathione
to form GSNO.
The enzyme GSNO reductase (GSNOR) reduces S-nitrosoglutathione (GSNO) to an unstable intermediate, S-hydroxylaminoglutathione, which then rearranges to form glutathione sulfinamide, or in the presence of GSH, forms oxidized glutathione (GSSG) and hydroxylamine. 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 generation of GSNO can serve as a stable and mobile NO pool which can effectively transduce NO signaling. 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 metal
s or target cellular proteins, often via S-nitrosylation
of cysteine
residues. Studies suggest that NO metabolism has a significant role in human cardiovascular and respiratory diseases as well as in immune tolerance during organ transplantation.
. Consistent with this therapeutic goal, a recent study showed that acute treatment with aerosolized GSNO was well-tolerated by cystic fibrosis patients.
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.
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. 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.
S-Nitrosothiol
S-Nitrosothiols, also known as thionitrites, are organic compounds or functional groups containing a nitroso group attached to the sulfur atom of a thiol...
(SNO) that plays a critical role in nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(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
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
chain propagation
Chain propagation
Chain propagation is a process in which a reactive intermediate is continuously regenerated during the course of a chemical reaction. In polymerization reaction, the reactive end-groups of a polymer chain react in each propagation step with a new monomer molecule transferring the reactive group to...
reactions, by reacting directly with ROO• radicals, yielding nitro
Nitro compound
Nitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group and is impure. The nitro group is one of the most common explosophores used globally...
derivatives as end products. NO is generated intracellularly by the nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
(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
Dinitrogen trioxide
Dinitrogen trioxide is the chemical compound with the formula N2O3. This deep blue liquid is one of binary nitrogen oxides. It forms upon mixing equal parts of nitric oxide and nitrogen dioxide and cooling the mixture below −21 °C :Dinitrogen trioxide is only isolable at low...
(N2O3). Some evidence suggests that both exogenous NO and endogenously derived NO from nitric oxide synthases can react with glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
to form GSNO.
The enzyme GSNO reductase (GSNOR) reduces S-nitrosoglutathione (GSNO) to an unstable intermediate, S-hydroxylaminoglutathione, which then rearranges to form glutathione sulfinamide, or in the presence of GSH, forms oxidized glutathione (GSSG) and hydroxylamine. 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 generation of GSNO can serve as a stable and mobile NO pool which can effectively transduce NO signaling. 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 metal
Transition metal
The term transition metal has two possible meanings:*The IUPAC definition states that a transition metal is "an element whose atom has an incomplete d sub-shell, or which can give rise to cations with an incomplete d sub-shell." Group 12 elements are not transition metals in this definition.*Some...
s or target cellular proteins, often via S-nitrosylation
Nitrosylation
Nitrosylation is a protein modification in which a nitrosyl group is post-translationally added to a protein.There is a range of enzymes that produce nitric oxide, and the frequent consequence of this production is nitrosylation....
of cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues. Studies suggest that NO metabolism has a significant role in human cardiovascular and respiratory diseases as well as in immune tolerance during organ transplantation.
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. 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 fibrosisCystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
. Consistent with this therapeutic goal, a recent study showed that acute treatment with aerosolized GSNO was well-tolerated by cystic fibrosis patients.
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
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(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.
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. 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.