Selenoglutathione Diselenide: Unique Redox Reactions in the GPx-Like Catalytic Cycle and Repairing of Disulfide Bonds in Scrambled Protein

Selenoglutathione (GSeH) is a selenium analogue of naturally abundant glutathione (GSH). In this study, this water-soluble small tripeptide was synthesized in a high yield (up to 98%) as an oxidized diselenide form, i.e., GSeSeG (<b>1</b>), by liquid-phase peptide synthesis (LPPS). Obtained <b>1</b> was applied to the investigation of the glutathione peroxidase (GPx)-like catalytic cycle. The important intermediates, i.e., GSe<sup>–</sup> and GSeSG, besides GSeO<sub>2</sub>H were characterized by <sup>77</sup>Se NMR spectroscopy. Thiol exchange of GSeSG with various thiols, such as cysteine and dithiothreitol, was found to promote the conversion to GSe<sup>–</sup> significantly. In addition, disproportionation of GSeSR to <b>1</b> and RSSR, which would be initiated by heterolytic cleavage of the Se–S bond and catalyzed by the generated selenolate, was observed. On the basis of these redox behaviors, it was proposed that the heterolytic cleavage of the Se–S bond can be facilitated by the interaction between the Se atom and an amino or aromatic group, which is present at the GPx active site. On the other hand, when a catalytic amount of <b>1</b> was reacted with scrambled 4S species of RNase A in the presence of NADPH and glutathione reductase, native protein was efficiently regenerated, suggesting a potential use of <b>1</b> to repair misfolded proteins through reduction of the non-native SS bonds.