Protein S-thiolation signal or damage

The kinetics of such reactions are controlled by steric and electrostatic effects as well as by the pKas of all thiol groups involved, since the actual nucleophilic 

From such figures, it can be concluded that in normal in vivo conditions, proteins which are under thermodynamic control of the glutathione redox buffer should be predominantly in the PSH form when Reaction (32) is feasible, whereas they will be predominantly in the P(S)2 form when Reaction (33) is feasible. Formation of protein mixed-disulfides PSSG is therefore likely to be of greater importance than that of P(S)2 in situations of oxidative stress. In such conditions however, non-steady-state concentrations of GSH and GSSG will often prevail and protein activities will be primarily under control of kinetic constraints. 

A large number of enzyme activities have been shown to be affected by protein S-thiolation with glutathione redox buffers in vitro (reviewed in ref. [271]). Extracellular and cell-surface proteins are commonly activated by the formation of intramolecular disulfides. Conversely, most of the responsive intracellular enzymes are down-regulated by the formation of mixed disulfides, with the interesting exception of enzymes involved in the delivery of free glucose. 

The discovery of non-specific disulfide reductases which are labile in aerobic cellular extracts suggests that kinetic constraints of thiol/disulfide exchange in vivo are very complex. One of such proteins is thioredoxin which behaves as a non-specific protein-disulfide reductase. Thioredoxin also works as a cofactor of sulfoxide reductases. The dithiol active site of thioredoxin sits on a protrusion of the protein surface [274], Thioredoxin is an ubiquitous protein whose molecular weight is about 12 KDa [274,275], It has been found in cytosolic and mitochondrial [276] compartments of animal cells, and it is partly bound to membranes. High contents in thioredoxin have been found in neurons, secretory and epithelial cells. Redox recycling of thioredoxin is insured by thioredoxin reductase, which has been identified in a variety of mammalian cells as a symmetrical dimer with a molecular weight of 116KDa[274]. Thioredoxin reductase is NADPH-specific, but it exhibits a very wide disulfide substrate specificity. 

Thioredoxin was shown to reduce the two interchain disulfides of insulin very efficiently around neutral pH and in the presence of either thioredoxin reductase and NADPH or lipoamide, lipoamide dehydrogenase and NADH [277,278], This reduction may be important in hormone action since the reduction of insulin disulfides is a prerequisite of proteolytic degradation of insulin. Thioredoxin has also been identified as the endogenous activator of the rat glucocorticoid receptor to a steroid-binding state [279]. Finally, recent data suggest that thioredoxin is secreted by immunocompetent cells and then behaves as an autocrine growth factor [280]. 

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