Molecular mechanisms and potential clinical significance of S-glutathionylation.
Protein S-glutathionylation, the reversible binding of glutathione to protein thiols (PSH), is involved in protein redox regulation, storage of glutathione, and protection of PSH from irreversible oxidation. S-Glutathionylated protein (PSSG) can result from thiol/disulfide exchange between PSH and GSSG or PSSG; direct interaction between partially oxidized PSH and GSH; reactions between PSH and S-nitrosothiols, oxidized forms of GSH, or glutathione thiyl radical. Indeed, thiol/disulfide exchange is an unlikely intracellular mechanism for S-glutathionylation, because of the redox potential of most Cys residues and the GSSG export by most cells as a protective mechanism against oxidative stress. S-Glutathionylation can be reversed, following restoration of a reducing GSH/GSSG ratio, in an enzyme-dependent or -independent manner. Currently, definite evidence of protein S-glutathionylation has been clearly demonstrated in few human diseases. In aging human lenses, protein S-glutathionylation increases; during cataractogenesis, some of lens proteins, including alpha- and beta-crystallins, form both mixed disulfides and disulfide-cross-linked aggregates, which increase with cataract severity. The correlation of lens nuclear color and opalescence intensity with protein S-glutathionylation indicates that protein-thiol mixed disulfides may play an important role in cataractogenesis and development of brunescence in human lenses. Recently, specific PSSG have been identified in the inferior parietal lobule in Alzheimer's disease. However, much investigation is needed to clarify the actual involvement of protein S-glutathionylation in many human diseases.
Dalle-Donne
Isabella
I
Department of Biology, University of Milan, Milan, Italy. quack@unimi.it
Milzani
Aldo
A
Gagliano
Nicoletta
N
Colombo
Roberto
R
Giustarini
Daniela
D
Rossi
Ranieri
R
D000818:Animals; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; D005978:Glutathione