Título:
Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis
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Autor:
Jobbagy, S.
Vitturi, D.A.
Salvatore, S.R.
Turell Novo, Lucía
Pires, M.F.
Kansanen, E.
Batthyány Dighiero, Carlos
Lancaster, J.R.
Freeman, B.A.
Schopfer, F.J.
Vitturi, D.A.
Salvatore, S.R.
Turell Novo, Lucía
Pires, M.F.
Kansanen, E.
Batthyány Dighiero, Carlos
Lancaster, J.R.
Freeman, B.A.
Schopfer, F.J.
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Tipo de documento:
Artículo
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Palabras clave:
Glutathione
Glutathione reductase
Electrophile
Nitrated fatty acid
Disulfide
Nrf2
Thiol
Oxidation-reduction (redox)
Glutathione reductase
Electrophile
Nitrated fatty acid
Disulfide
Nrf2
Thiol
Oxidation-reduction (redox)
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Año de publicación:
2019
Contenido:
Resumen:
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.
Descripción:
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Editorial:
Elsevier
EN:
Redox Biology, 2019, 21:101050
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Citación:
Jobbagy, S., Vitturi, D., Salvatore, S. y otros. "Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis". Redox Biology. [en línea] 2019, 21:101050. 15 h. DOI: 10.1016/j.redox.2018.11.008
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ISSN:
2213-2317
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Licencia:
Licencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0)
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| Ficheros | Descripción | Tamaño | Formato | ||
|---|---|---|---|---|---|
| 10.1016j.redox.2018.11.008.pdf | — | 3 MB | Adobe PDF |