Abstract
Post-translational S-glutathionylation occurs through the reversible addition of a proximal donor of glutathione to thiolate anions of cysteines in target proteins, where the modification alters molecular mass, charge, and structure/function and/or prevents degradation from sulfhydryl overoxidation or proteolysis. Catalysis of both the forward (glutathione S-transferase P) and reverse (glutaredoxin) reactions creates a functional cycle that can also regulate certain protein functional clusters, including those involved in redox-dependent cell signaling events. For translational application, S-glutathionylated serum proteins may be useful as biomarkers in individuals (who may also have polymorphic expression of glutathione S-transferase P) exposed to agents that cause oxidative or nitrosative stress.
Highlights
Thiol Modification by RNSRNS include moieties such as nitric oxide (NO) and NO-derived compounds, nitroxyl anion (NOϪ, HNO), nitrosonium cation (NOϩ), higher oxides of nitrogen (N2O, NO2, N2O3), peroxynitrite (ONOOϪ/ONOOH), S-nitrosothiols (RSNO), and dinitrosyl iron complexes ((RSϪ)2Feϩ(NOϩ)2 . . . (ϪSR)2)Ϫ) [24]
S-Glutathionylation targets cysteines in a basic environment perhaps in close three-dimensional proximity to Arg, His, or Lys residues
A literature review reveals some clustering of function and includes enzymes with catalytically important cysteines; cytoskeletal proteins; signaling proteins; transcription factors; Ras proteins; protein folding and degradation; ion channels, calcium pumps, and binding proteins; and energy metabolism and glycolysis
Summary
RNS include moieties such as nitric oxide (NO) and NO-derived compounds, nitroxyl anion (NOϪ, HNO), nitrosonium cation (NOϩ), higher oxides of nitrogen (N2O, NO2, N2O3), peroxynitrite (ONOOϪ/ONOOH), S-nitrosothiols (RSNO), and dinitrosyl iron complexes ((RSϪ)2Feϩ(NOϩ)2 . . . (ϪSR)2)Ϫ) [24]. The thiol deprotonates to a thiolate anion, which attacks the sulfhydryl of intracellular GSSG, with the subsequent formation of disulfide (pathway 1). There are reports that Grx can catalyze GSSG-dependent S-glutathionylation of proteins such as actin, GAPDH, and protein-tyrosine phosphatase 1B by an alternative mechanism involving 1⁄7OH-mediated GSH thiol radical generation under hypoxia [29]. High intracellular GSH concentrations can shift the equilibrium of the reaction with NO to GSSG, but during nitrosative stress, certain cell compartments can harbor high levels of GSNO. Under such conditions, GSNO may contribute to protein nitrosylation and/or S-glutathionylation [9, 10]. The specificity of GSNO-mediated post-translational modifications depends on the microenvironment of the target cysteine within protein tertiary and quaternary structures
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