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Modelling the Inhibition of Selenoproteins by Small Molecules Using Cysteine and Selenocysteine Derivatives

Reddy, Kishorkumar M. and Mugesh, Govindasamy (2019) Modelling the Inhibition of Selenoproteins by Small Molecules Using Cysteine and Selenocysteine Derivatives. In: CHEMISTRY-A EUROPEAN JOURNAL, 25 (37). pp. 8875-8883.

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Official URL: https://dx.doi.org/10.1002/chem.201901363


Small molecule-based electrophilic compounds such as 1-chloro-2,4-dinitrobenzene (CDNB) and 1-chloro-4-nitrobenzene (CNB) are currently being used as inhibitors of cysteine- and selenocysteine-containing proteins. CDNB has been used extensively to determine the activity of glutathione S-transferase and to deplete glutathione (GSH) in mammalian cells. Also, CDNB has been shown to irreversibly inhibit thioredoxin reductase (TrxR), a selenoenzyme that catalyses the reduction of thioredoxin (Trx). Mammalian TrxR has a C-terminal active site motif, Gly-Cys-Sec-Gly, and both the cysteine and selenocysteine residues could be the targets of the electrophilic reagents. In this paper we report on the stability of a series of cysteine and selenocysteine derivatives that can be considered as models for the selenoenzyme-inhibitor complexes. We show that these derivatives react with H2O2 to generate the corresponding selenoxides, which undergo spontaneous elimination to produce dehydroalanine. In contrast, the cysteine derivatives are stable towards such elimination reactions. We also demonstrate, for the first time, that the arylselenium species eliminated from the selenocysteine derivatives exhibit significant redox activity by catalysing the reduction of H2O2 in the presence of GSH (GPx (glutathione peroxidase)-like activity), which suggests that such redox modulatory activity of selenium compounds may have a significant effect on the cellular redox state during the inhibition of selenoproteins.

Item Type: Journal Article
Additional Information: copyright for this articles belongs to WILEY-V C H VERLAG GMBH
Keywords: amino acids; enzymes; inhibitors; reaction mechanisms; selenium
Department/Centre: Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited: 29 Aug 2019 06:30
Last Modified: 29 Aug 2019 06:30
URI: http://eprints.iisc.ac.in/id/eprint/63424

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