Sulfiredoxin: a potential therapeutic agent?

Abstract

The importance of antioxidants in maintaining homeostasis has long been accepted and includes antioxidant proteins such as, peroxiredoxin (Prx), superoxide dismutase and glutathione S transferases. Sulfiredoxin (Srx) is a recently identified antioxidant protein with a role in signaling through catalytic reduction of oxidative modifications. It was first characterized for its regulation of Prx(s) through reduction of the conserved cysteine from sulfinic to sulfenic acid, thereby impacting the role of Prx in regulation of downstream transcription factors and kinase signaling pathways. Furthermore, the reduction of sulfinic to sulfenic acid prevents further oxidation of the conserved cysteine residue to sulfonic acid, the end result of which is degradation. Srx also has a role in the reduction of glutathionylation a post-translational, oxidative modification that occurs on numerous proteins and has been implicated in a wide variety of pathologies, including Parkinson's disease. The regulation of glutathionylation/deglutathionylation (or thiol switch) has been likened to phosphorylation/dephosphorylation, another post-translational modification involved in the regulation of signaling pathways. Unlike, the reduction of Prx over-oxidation, Srx-dependent deglutathionylation appears to be non-specific. Deglutathionylation of multiple proteins has been observed both in vitro and in vivo in response to oxidative and/or nitrosative stress. This review discusses Srx as a novel antioxidant, and focuses on its potential role in the regulation of glutathionylation/deglutathionylation pathways, that have been implicated in a growing number of disease states.

Fig. 1.

Differential regulation of ASK1 by Trx, Grx and GSTμ. ASK1 is in complex with reduced Trx, Grx and GSTμ and is inactive under basal conditions. ROS/RNS, generated by a plethora of different stresses, leads to the activation of ASK1 through the dissociation of one or another of its small redox molecule inhibitors. The dissociation occurs concurrently with the formation of a disulfide bond with Trx, Grx or GSTμ. The activation of ASK1 results in the activation of a cascade, the end point of which is the initiation of apoptosis or stress response.

Fig. 2.

Scheme of cysteine oxidation. The oxidation of a sulfur residue within the amino acid cysteine can result in the formation of a cysteine radical or a sulfenic, sulfinic or sulfonic acid derivative (the latter of which is irreversible). Reduction of the sulfinic to the sulfenic acid derivative in Prx is known to occur through the action of Srx. The oxidation of the sulfur residue in GSH results in the formation of glutathione sulfenate. This reactive molecule can react with a reduced protein cysteine residue (Cys–SH), either directly or indirectly through the formation of glutathione disulfide S-oxide, to form a protein mixed disulfide. Studies have also implicated Srx in the reduction of glutathionylated proteins (Cys–S–SG).