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Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis

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Date
2019
Author(s)
Jobbagy, Soma
Vitturi, Dario A
Salvatore, Sonia R
Turell, Lucía
Pires, Maria F
Kansanen, Emilia
Batthyany, Carlos
Lancaster, Jack R Jr
Freeman, Bruce A
Schopfer, Francisco
Unique identifier
10.1016/j.redox.2018.11.008
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Citation
Jobbagy, Soma. Vitturi, Dario A. Salvatore, Sonia R. Turell, Lucía. Pires, Maria F. Kansanen, Emilia. Batthyany, Carlos. Lancaster, Jack R Jr. Freeman, Bruce A. Schopfer, Francisco. (2019). Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis.  Redox biology, 21, 101050. 10.1016/j.redox.2018.11.008.
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CC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
Abstract

Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state by glutathione reductase (GR). Nitro oleic acid (NO2-OA) is an electrophilic fatty acid formed under digestive and inflammatory conditions that both reacts with GSH and induces its synthesis upon activation of Nrf2 signaling. The effects of NO2-OA on intracellular GSH homeostasis were evaluated. In addition to upregulation of GSH biosynthesis, we observed that NO2-OA increased intracellular GSSG in an oxidative stress-independent manner. NO2-OA directly inhibited GR in vitro by covalent modification of the catalytic Cys61, with kon of (3.45 ± 0.04) × 103 M−1 s−1, koff of (4.4 ± 0.4) × 10−4 s−1, and Keq of (1.3 ± 0.1) × 10−7 M. Akin to NO2-OA, the electrophilic Nrf2 activators bardoxolone-imidazole (CDDO-Im), bardoxolone-methyl (CDDO-Me) and dimethyl fumarate (DMF) also upregulated GSH biosynthesis while promoting GSSG accumulation, but without directly inhibiting GR activity. In vitro assays in which GR was treated with increasing GSH concentrations and GSH depletion experiments in cells revealed that GR activity is finely regulated via product inhibition, an observation further supported by theoretical (kinetic modeling of cellular GSSG:GSH levels) approaches. Together, these results describe two independent mechanisms by which electrophiles modulate the GSH/GSSG couple, and provide a novel conceptual framework to interpret experimentally determined values of GSH and GSSG.

Subjects
glutathione   glutathione reductase   electrophile   nitrated fatty acid   disulfide   Nrf2   thiol   oxidation-reduction (redox)   
URI
https://erepo.uef.fi/handle/123456789/7430
Link to the original item
http://dx.doi.org/10.1016/j.redox.2018.11.008
Publisher
Elsevier BV
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  • Terveystieteiden tiedekunta [1324]
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