| Popis: |
Background: Thioredoxin reductase (TrxR), one of the representative selenoenzymes, is an important antioxidant enzyme suppressing oxidative stress in living organisms. At the active site of human TrxR, the presence of a Sec•••His•••Glu catalytic triad was previously suggested. Method. In this study, a short selenopeptide mimicking this plausible triad, i.e., H-CUGHGE-OH (1), was designed, synthesized, and evaluated for the TrxR-like catalytic activity. Method: In this study, a short selenopeptide mimicking this plausible triad, i.e., H-CUGHGE-OH (1), was designed, synthesized, and evaluated for the TrxR-like catalytic activity Results: The molecular simulation in advance by REMC/SAAP3D predicted the preferential formation of Sec•••His•••Glu hydrogen bonding networks in the aqueous solution. Indeed, a significant antioxidant activity was observed for 1 in the activity assay using NADPH as a reductant and H2O2 as a substrate. Tracking the reaction between 1 and GSH by 77Se NMR revealed a reductive cleavage of the selenosulfide (Se-S) bond to generate the diselenide species. The observation suggested that in the transiently formed mixed Se-S intermediate, the NH•••Se hydrogen bond between the Sec and His residues leads a nucleophilic attack of the second thiol molecule not to the intrinsically more electrophilic Se atom but to the less electrophilic S atom of the Se-S bond. Ab initio calculations for the complex between MeSeSMe and an imidazolium ion at the MP2/6-31++G(d,p) level demonstrated that NH•••Se and NH•••S hydrogen bonds are equally favorable as the interaction modes. Thus, importance of the relative spatial arrangement of the Se-S bond with respect to the imidazole ring was suggested for the exertion of the TrxR-like catalytic activity. Conclusion: The proposed umpolung effect of NH•••Se hydrogen bond on the reactivity of a Se-S bond will be a useful tool for developing efficient TrxR models with high redox catalytic activity. |
