Abstract
Oxidation of the antioxidant glutathione (GSH) to a disulfide (GSSG) has long been an indicator of oxidative stress. GSH is also critical in the detoxification of xenobiotics (drugs, pollutants, carcinogens) through a broad range of reactions with GSH- dependent enzymes containing a redox sensitive cysteine (Cys) residue that undergoes reversible oxidation and reduction at the active site: GSH reductase (GR), glutaredoxin (Grx), and the families of GSH peroxidases (Gpxs) and GSH-S-transferases (GSTs). GSH and GSSG are also involved in many cellular processes termed S-glutathionylation where disulfide bonds are formed with protein Cys residues that subsequently alter enzymatic activity or protein function. The equipoise of GSH/GSSG is pivotal in signal transduction pathways mediated by reaction of reactive oxygen species (ROS) with crucial protein Cys residues. ROS-dependent signaling also involves reduced/oxidized thiol pairs including thioredoxin (Trx-SH/Trx-SS) and Cys with its oxidized form cystine (CySS). Although not in equilibrium, these thiol/disulfide couples are organized into redox circuits with cross-talk. When these redox circuits are disrupted, critical redox active Cys sites become oxidized and protein functions are perturbed. Understanding the roles of redox signaling and redox homeostasis for GSH and other thiol pairs in the responses of the organelle or cell to redox-active chemicals is central to determining the effects of such chemicals on macromolecular structure, regulation, and signaling during the life cycle. Through a better mechanistic understanding, the roles for redox homeostasis of thiol pairs like GSH in the resilience and adaptability to diet and environmental exposures are likely to emerge.
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Abbreviations
- Cys:
-
Cysteine
- CySS:
-
Cystine
- GCL:
-
γ-Glutamylcysteine Ligase
- GGT:
-
γ-Glutamyl transferase
- GSH:
-
Glutathione (reduced)
- GSSG:
-
Glutathione (oxidized)
- Gpx:
-
Glutathione Peroxidase
- GR:
-
Glutathione Reductase
- GS:
-
Glutathione Synthase
- Grx:
-
Glutaredoxin
- GST:
-
Glutathione S-transferase
- H2O2 :
-
Hydrogen Peroxide
- Prdx:
-
Peroxiredoxin
- ROS:
-
Reactive oxygen species
- Trx:
-
Thioredoxin
- TrxR:
-
Thioredoxin Reductase
- VOC:
-
Volatile Organic Compounds
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Brown, L.A.S., Jones, D.P. (2015). Glutathione and Thiols. In: Roberts, S., Kehrer, J., Klotz, LO. (eds) Studies on Experimental Toxicology and Pharmacology. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-19096-9_7
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