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Current Chemical Biology

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ISSN (Print): 2212-7968
ISSN (Online): 1872-3136

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Research Article

Antioxidant Activity of a Selenopeptide Modelling the Thioredoxin Reductase Active Site is Enhanced by NH···Se Hydrogen Bond in the Mixed Selenosulfide Intermediate

Author(s): Michio Iwaoka*, Hajime Oba, Kotoi Matsumura, Shuhei Yamanaka, Shingo Shimodaira, Shuichi Kusano and Tatsuya Asami

Volume 16, Issue 1, 2022

Published on: 13 June, 2022

Page: [44 - 53] Pages: 10

DOI: 10.2174/2212796816666220415142301

Price: $65

Abstract

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.

Methods: 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, 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, the 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.

Keywords: Selenoenzyme mimics, selenocysteine, liquid-phase peptide synthesis, peroxidase activity, selenosulfide bond, umpolung effect, glutathione peroxidase.

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