Causes and Consequences of Cysteine S-Glutathionylation

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.S-Glutathionylation targets cysteines in a basic environment (low pK a ) perhaps in close three-dimensional proximity to Arg, His, or Lys residues. Reports of reversible S-glutathionylation emerged as early as 1985 (1), but in concert with understanding the importance of reactive oxygen/nitrogen species (ROS/ RNS) 2 as second messengers, publications have increased substantially over the past 10 years. ROS/RNS signaling operates through a set of post-translational protein modifications that are discrete, site-specific, and reversible. Certain proteins undergo reversible chemical changes in response to altered localized redox potential. Among the most susceptible redoxsensitive targets are thiol (-SH) groups on cysteines. Signaling events are facilitated through redox-active proteins when one or more cysteines can exist as reactive thiolate anions. These cysteines are more nucleophilic and become susceptible to attack by GSH.Oxygen-based metabolism is arguably the most efficient and evolved method for producing energy from nutrients, but ROS

The Metalloid Reductase of Pseudomonas Moravenis Stanleyae Conveys Nanoparticle Mediated Metalloid Tolerance

“…[31][32][33][34] This reversible post-translation modification is the binding of glutathione to an unpaired cysteine residue. 35 Such modification alters enzyme activity, presumably as a regulation mechanism.…”

Glutathionylation of the Aquaporin-2 Water Channel

“…Redox PTMs have emerged as important molecular signals described in all organisms. Increasing evidence revealed that ROS and reactive nitrogen species function as signaling components transducing extracellular or intracellular information and elaborating highly selective responses by promoting PTMs of thiol residues on target proteins (3,20). Glutathione can be considered one of the major cellular antioxidant molecules that are continuously converted into the reduced form of GSH.…”

How widespread is stable protein S-nitrosylation as an end-effector of protein regulation?

“…Additionally, acetylcholine increased cellular protein S-glutathiolation which was attenuated by inhibition of endothelial NOS [81]. As well as directly regulating protein function, S-thiolation is also thought to protect proteins from oxidative stress, possibly by abrogating cysteine hyperoxidation to the sulfinic or sulfonic acid states [82,83]. Mechanistic studies suggest that during nitrosative stress protein S-glutathiolation is kinetically more likely via a protein S-nitrosothiol intermediate than an exchange reaction of the protein thiol with GSSG [84].…”