Disease relevance of SRXN1

• 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 [1].

High impact information on SRXN1

• Human sulfiredoxin contains one cysteine residue (Cys(99)) that is conserved in all family members [2].
• Actin and protein tyrosine phosphatase 1B were identified in vitro as targets of sulfiredoxin 1 (Srx1)-dependent deglutathionylation and confirmed in vivo by two-dimensional gel electrophoresis analysis [2].
• Among many proteins with cysteine sulfinic acid (Cys-SO2H) residues, the sulfinic forms of certain peroxiredoxins (Prxs) are selectively reduced by sulfiredoxin (Srx) in the presence of ATP [3].
• The presence of the sulfinic form (but not the reduced form) of PrxI induces the conserved cysteine of Srx to take the gamma-phosphate of ATP and then immediately transfers the phosphate to the sulfinic moiety of PrxI to generate a sulfinic acid phosphoryl ester (Prx-Cys-S(=O)OPO3(2-)) [3].
• Comparison with the homologous yeast structure and other longin domains reveals a conserved adjustable hydrophobic surface within SRX which is of central importance for the SRbeta-GTP:SRX interface [4].

Biological context of SRXN1

• Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine [5].
• We show that Srx has significant sequence and structural similarity to a functionally unrelated protein, ParB, a DNA-binding protein with a helix-turn-helix (HTH) domain which is involved in chromosome partitioning in bacteria [6].
• Evolution of eukaryotic cysteine sulfinic acid reductase, sulfiredoxin (Srx), from bacterial chromosome partitioning protein ParB [6].

Associations of SRXN1 with chemical compounds

• All Srx enzymes contain a conserved cysteine residue [3].
• Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-cys peroxiredoxins [7].
• Both glutathione and thioredoxin are potential physiological electron donors for the Srx reaction, given that their Km values (1.8 mM and 1.2 microM, respectively) are in the range of their intracellular concentrations, and the Vmax values obtained with the two reductants were similar [5].
• We observed the exclusive formation of a thiosulfinate linkage between Prx and Srx (k = 1.4 min(-1)) that collapses to the disulfide-bonded Srx-Prx species (k = 0.14 min(-1)) [8].

Other interactions of SRXN1

• 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 [1].
• Unlike, the reduction of Prx over-oxidation, Srx-dependent deglutathionylation appears to be non-specific [1].
• Although Srx reduces sulfinic Prx III in vitro, it remains unclear whether the reduction of Prx III in cells is actually mediated by Srx [9].

Analytical, diagnostic and therapeutic context of SRXN1

• Using two-dimensional gel electrophoresis, we identified multiple protein targets in vivo that are deglutathionylated by sulfiredoxin following oxidative and/or nitrosative stress [2].

References