Cellular S-denitrosylases: Potential role and interplay of Thioredoxin, TRP14, and Glutaredoxin systems in thiol-dependent protein denitrosylation

Stability of S‐nitrosothiols and S‐nitrosylated proteins: A struggle for cellular existence!

“…It is also interesting to note that S-nitrosylation of proteins at specific cysteine residues dependent upon several biochemical and biophysical factors including pKa values of specific thiol (s), microenvironment (hydrophobic or hydrophilic), structural accessibility, subcellular localization, redox potential, redox status and many more. 1,79 The classical example discussed in the text is the serum abundant protein albumin which possesses 35 cysteine residues. However, only one residue (Cys34) out of 35 particularly participates in S-nitrosylation.…”

“…Several researchers also agree that denitrosylation of cellular proteins is a concerted mechanism which involves both nonenzymatic (GSH) and enzymatic antioxidant (Trx and glutaredoxin [Grx] systems) systems to work together that can complement each other having different substrate specificities, mechanism, local availability to maintain a reducing environment in the cell. 1 It was also reported that Trx catalyzed the denitrosylation of cytosolic PSNOs from HepG2 cells cooperatively with GSH. 61 Nonetheless, under nitrosative stress stimuli, the proportion of PSNOs in the cell allows the proteins to remain inside the cell in Abbreviation: GSH, reduced glutathione.…”

“…Several denitrosylases (both nonenzymatic and enzymatic) have been documented. 1 Glutathione (GSH) is the most abundant tripeptide (cys-gly-glu) and nonenzymatic antioxidant present in the cell that participates in reducing the S-NO bonds to decompose cellular RSNOs/ PSNOs. The appreciable concentration of GSH present in the cell (5-10 mM) facilitates its denitrosylation and disulfide reduction activity to maintain an overall reducing environment in the cell.…”

“…In recent years, the denitrosylation mechanism served by cellular antioxidants has gained significant momentum. Several denitrosylases (both nonenzymatic and enzymatic) have been documented 1 . Glutathione (GSH) is the most abundant tripeptide (cys‐gly‐glu) and nonenzymatic antioxidant present in the cell that participates in reducing the S‐NO bonds to decompose cellular RSNOs/PSNOs.…”

“…Over the years, there has been a significant expansion of knowledge in the field of NO signaling mediated by S‐nitrosylation and its physiological importance. The mechanism of S‐nitrosylation involves docking of NO to thiol functions of 1 proteins/nonprotein thiols and thereby formation of protein S‐nitrosothiols that directly regulate the downstream effector functions. However, the formation and stability of S‐nitrosothiols (RSNOs) and S‐nitrosylated proteins (PSNOs) has been a matter of recent controversy.…”