S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

Abstract

S-nitrosylation of proteins occurs as a consequence of the derivatization of cysteine thiols with nitric oxide (NO) and is often associated with diseases and protein malfunction. Aberrant S-nitrosylation, in addition to other genetic and epigenetic factors, has gained rapid importance as a prime cause of various metabolic, respiratory, and cardiac disorders, with a major emphasis on cancer and neurodegeneration. The S-nitrosoproteome, a term used to collectively refer to the diverse and dynamic repertoire of S-nitrosylated proteins, is relatively less explored in the field of redox biochemistry, in contrast to other covalently modified versions of the same set of proteins. Advancing research is gradually unveiling the enormous clinical importance of S-nitrosylation in the etiology of diseases and is opening up new avenues of prompt diagnosis that harness this phenomenon. Ever since the discovery of the two robust and highly conserved S-nitrosoglutathione reductase and thioredoxin systems as candidate denitrosylases, years of rampant speculation centered around the identification of specific substrates and other candidate denitrosylases, subcellular localization of both substrates and denitrosylases, the position of susceptible thiols, mechanisms of S-denitrosylation under basal and stimulus-dependent conditions, impact on protein conformation and function, and extrapolating these findings towards the understanding of diseases, aging and the development of novel therapeutic strategies. However, newer insights in the ever-expanding field of redox biology reveal distinct gaps in exploring the crucial crosstalk between the redoxins/major denitrosylase systems. Clarifying the importance of the functional overlap of the glutaredoxin, glutathione, and thioredoxin systems and examining their complementary functions as denitrosylases and antioxidant enzymatic defense systems are essential prerequisites for devising a rationale that could aid in predicting the extent of cell survival under high oxidative/nitrosative stress while taking into account the existence of the alternative and compensatory regulatory mechanisms. This review thus attempts to highlight major gaps in our understanding of the robust cellular redox regulation system, which is upheld by the concerted efforts of various denitrosylases and antioxidants.

Clioquinol rescues yeast cells from Aβ42 toxicity via the inhibition of oxidative damage

“…Trx and Grx systems complement the antioxidant activity of GSH and are regulated by it. [57] Conversely, Grx and Trx are indispensable for regenerating GSH. [58,59] Further research is needed on how CQ maintains GSH steady-state through these two systems.…”

Glutathione and Glutaredoxin—Key Players in Cellular Redox Homeostasis and Signaling

“…Rajib Sengupta and coworkers have a special interest in S-nitrosylation as a regulatory mechanism. In their review that contributed to this Special Issue [ 82 ], they focused on the mechanisms of denitrosylation of protein-SNO and the enzymes that catalyze it, analogous to the catalysis of deglutathionylation by glutaredoxin. S-nitrosylated proteins can be denitrosylated by GSH within the range of the physiological concentrations of GSH (5–10 mM), except for a few proteins, such as caspase 3.…”