Emerging Regulatory Paradigms in Glutathione Metabolism

Abstract

One of the hallmarks of cancer is the ability to generate and withstand unusual levels of oxidative stress. In part, this property of tumor cells is conferred by elevation of the cellular redox buffer glutathione. Though enzymes of the glutathione synthesis and salvage pathways have been characterized for several decades, we still lack a comprehensive understanding of their independent and coordinate regulatory mechanisms. Recent studies have further revealed that overall central metabolic pathways are frequently altered in various tumor types, resulting in significant increases in biosynthetic capacity, and feeding into glutathione synthesis. In this review, we will discuss the enzymes and pathways affecting glutathione flux in cancer, and summarize current models for regulating cellular glutathione through both de novo synthesis and efficient salvage. In addition, we examine the integration of glutathione metabolism with other altered fates of intermediary metabolites, and highlight remaining questions about molecular details of the accepted regulatory modes.

Exploring the neuroprotective effects of ginkgolides injection in a rodent model of cerebral ischemia–reperfusion injury by GC–MS based metabolomic profiling

“…These metabolic changes suggested a block in neuro-astrocytic glutamate-glutamine cycle and GABA shunt, and lead to functional deafferentation in ischemia regions [41]. GSH, an endogenous antioxidant, not only plays an important role in detoxification but also participates in the neuronal uptake of amino acids via the γ-glutamyl cycle [42,43]. The decrease in the level of ribose-5-phosphate indicated the pentose phosphate pathway (PPP) was inhibited, which further resulted in GSH depletion (verified in this work) as NADPH generated by PPP is the essential redox equivalent for GSH/GSSG cycling.…”

Simultaneous quantitation of oxidized and reduced glutathione via LC-MS/MS: An insight into the redox state of hematopoietic stem cells

“…Glutathione, γ-L-glutamyl-L-cysteinylglycine, (GSH) is an endogenous tripeptide involved in many cellular processes including apoptosis, cellular detoxification, and redox signaling[1, 2]. Currently, GSH is thought of as a major cellular reducing agent, with high intracellular concentrations reported to range from 0.5–10 mM, that aids in protection from ROS mediated injury [3–5].…”

“…GSH activity is subsequently regulated via cycling the cysteinyl thiol (pKa= 9.2) through oxidized and reduced states. GSH-mediated cellular detoxification may be accomplished by the direct conjugation of GSH, to xenobiotics and other endogenously produced small molecules via glutathione-S-transferase (GST) activity or through the action of glutathione peroxidase (GPx), which reduces hydrogen peroxide while GSH is co-oxidized to its disulfide form (GSSG)[1, 2, 7, 8]. Additionally, GSH may reversibly modulate cellular redox signaling via direct glutathionylation of thiol groups within redox sensitive signaling proteins.…”

Transcriptomic Profiling of MDA-MB-231 Cells Exposed to Boswellia Serrata and 3-O-Acetyl-Β-Boswellic Acid; ER/UPR Mediated Programmed Cell Death

“…While discussing all the changes in the transcriptome initiated by 3-OAβBA and BSE are beyond the scope of this paper, noteworthy is the rise in CHAC1, which is involved in the degradation of glutathione (62,63) reported to occur in parallel to rise of ATF4-ATF3-CHOP PERK and the phosphorylation of EIF2α, where its rise creates vulnerability of cancer cells to the losses of glutathione associated with radiation and oxidative insult (64, 65) also rendering losses on glutathione detoxification systems (66).…”