The Role of Methionine Sulfoxide Reductase in Redox Signaling

Abstract

This letter concerns the article published recently by Lim et al. (1). The mechanism of methionine sulfoxide reductases begins with formation of a sulfenic acid on the catalytic Cys. Most of the methionine sulfoxide reductases (Msr) then form only one intradisulfide bond via the attack of a recycling Cys. The disulfide bond is then reduced by thioredoxin to regenerate the Msr. Kinetic experiments clearly demonstrated that the rate-limiting step is associated with the Trx-recycling process, whereas the rate of formation of the intradisulfide bond is limited by that of the sulfenic acid intermediate (2). Therefore, the sulfenic acid never accumulates in vivo whatever the subclass of MsrA/B. Recently, Levine and coworkers determined a pKapp of 7.2 for the catalytic Cys of the mouse MsrA (1). In fact, the pKapp can vary from 9.5 in Neisseria meningitidis (3), a value determined using 2-PDS as a probe, to 7.2 in mouse MsrA, indicating a catalytic Cys environment depending on the MsrA. The reaction of H2O2 can give two isomers of the sulfenic acid function, e.g. one with the OH oriented within the active site and strongly stabilized by a network of hydrogen bond interactions that will favor formation of disulfide bond (4) and the other one oriented in the opposite direction within the solvent, not stabilized, and thus whose population will shift to the first one. Therefore, a role of Msr, present in the three kingdoms, in redox signaling is excluded because the sulfenic acid never accumulates and its formation rate of 32 m−1 s−1 is low compared with 105–107 m−1 s−1 in peroxiredoxins (5).