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 PSNOs within the cell and attempts to put an end to the controversy. This review illustrates critical points including comparative bond dissociation energies of S‐NO bond, the half‐life of S‐nitrosothiols and PSNOs, cellular concentrations of PSNOs, X ray crystallographic studies on PSNOs, and stability of PSNOs at physiological concentration of antioxidants. These logical evidence cumulatively support the endogenous stability and inevitable existence of PSNOs/RSNOs within the cell that directly regulate the functionality of proteins and provide valuable insight into understanding stable S‐nitrosylation mediated cell signaling.