ATP-dependent reduction of cysteine–sulphinic acid by S. cerevisiae sulphiredoxin

Proteins contain thiol-bearing cysteine residues that are sensitive to oxidation, and this may interfere with biological function either as ‘damage’ or in the context of oxidant-dependent signal transduction. Cysteine thiols oxidized to sulphenic acid are generally unstable, either forming a disulphide with a nearby thiol or being further oxidized to a stable sulphinic acid1,2. Cysteine–sulphenic acids and disulphides are known to be reduced by glutathione or thioredoxin in biological systems, but cysteine–sulphinic acid derivatives have been viewed as irreversible protein modifications. Here we identify a yeast protein of relative molecular mass Mr = 13,000, which we have named sulphiredoxin (identified by the US spelling ‘sulfiredoxin’, in the Saccharomyces Genome Database), that is conserved in higher eukaryotes and reduces cysteine–sulphinic acid in the yeast peroxiredoxin Tsa1. Peroxiredoxins are ubiquitous thiol-containing antioxidants that reduce hydroperoxides3,4,5 and control hydroperoxide-mediated signalling in mammals6,7,8. The reduction reaction catalysed by sulphiredoxin requires ATP hydrolysis and magnesium, involving a conserved active-site cysteine residue which forms a transient disulphide linkage with Tsa1. We propose that reduction of cysteine–sulphinic acids by sulphiredoxin involves activation by phosphorylation followed by a thiol-mediated reduction step. Sulphiredoxin is important for the antioxidant function of peroxiredoxins, and is likely to be involved in the repair of proteins containing cysteine–sulphinic acid modifications, and in signalling pathways involving protein oxidation.