S-Glutathionylation: A Redox-Sensitive Switch Participating in Nitroso-Redox Balance

Chen et alNature . 2010;468:1115–1118Cysteine side chains of proteins are being increasingly appreciated as the site of major posttranslational modifications that exert profound degrees of protein regulation.1,–,3 One of the consequences of tissue nitroso-redox imbalance is a process by which regulatory thiols switch from a state of physiologic regulation by S-nitrosylation to a state of dysregulated function because of oxidation.4,5 A key example of this is well described for regulation of the ryanodine receptor/Ca2+- release channels 1 and 2.6,–,13The interaction between reactive oxygen species (ROS) and reactive nitrogen species can lead to the inactivation of nitric oxide (NO), formation of further highly reactive nitrogen species, such as peroxynitrite, or the dysregulation of biological signaling processes via irreversible oxidative modification of protein thiol moieties.5 It is increasingly recognized that an important posttranslational modification of thiols within this spectrum of biochemical reactions is that of S-glutathionylation.14,–,16 In a recent report in Nature , Chen and colleagues17 describe a fascinating feed forward system, in which a redox shift enhances S-glutathionylation of endothelial NO synthase (eNOS or NOS3) (Figure). This modification, in turn, shifts eNOS from an NO-generating enzyme to a producer of ROS.Figure. Schematic representation of oxidative stress-mediated S-glutathionylation …