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

Abstract

Nitric oxide is a well-known gasotransmitter molecule that covalently docks to sulfhydryl groups of proteins resulting in S-nitrosylation of proteins and nonprotein thiols that serve a variety of cellular processes including cGMP signaling, vasodilatation, neurotransmission, ion-channel modulation, and cardiac signaling. S-nitrosylation is an indispensable modification like phosphorylation that directly regulates the functionality of numerous proteins. However, recently there has been a controversy over the stability of S-nitrosylated proteins (PSNOs) within the cell. It has been argued that PSNOs formed within the cell is a transient intermediate step to more stable disulfide formation and disulfides are the predominant end effector modifications in NO-mediated signaling. The present article accumulates state-of-the-art evidence from numerous research that strongly supports the very existence of How to cite this article: Chatterji A, Sengupta R.

S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

“…Similarly, about a hundred proteins are capable of S-(de)nitrosylation, another highly stringent post-translational redox modification within the intracellular milieu, where both the S-nitrosylated as well as denitrosylated proteins are responsible for cellular NO-signaling. Very few protein-SNOs are stable or are not denitrosylated in physiological GSH concentrations; these proteins include caspase-3, α-tubulin, β-tubulin, collapsin response mediator protein-2, Creatine kinase (B chain), extracellular signal-regulated kinase-2, glutathione-S-transferase (GST) pi, glyceraldehyde-3-phosphate dehydrogenase (GADPH), hemoglobin (β chain), pyruvate kinase, and Prx6 [ 29 , 55 , 56 , 57 ]. Amongst all these protein-SNOs, the most prominent is caspase-3, which cannot be denitrosylated by GSH or GSNOR, but exclusively by Trx; this proves the S-nitrosylation of this apoptotic protein by NO donors, but the failure of the activity regeneration in the absence of Trx, which again establishes a link between caspases and cancer and eliminates the direct role of GSH in the same, while indirectly GSH as well as reduced human Trxs have the potential to denitrosylated S-nitroso thioredoxins, inactivating caspase-3, linking GSH to the apoptotic pathways [ 12 , 58 ].…”

“…This discussion becomes especially pertinent when viewing the intracellular redox milieu from a biochemical perspective. Reduced GSH efficiently denitrosylates small molecule nitrosothiols and a large percentage of PSNOs; however, a subset of PSNOs continues to be stable, even in the presence of cellular levels of GSH [ 56 , 57 ]. This suggests the presence of preferential selectivity or specificity of one substrate over the other by various denitrosylases.…”