Glutathione Degradation Is a Key Determinant of Glutathione Homeostasis

Baudouin‐Cornu, Peggy; Lagniel, Gilles; Kumar, Chitranshu; Huang, Meng‐Er; Labarre, Jean

doi:10.1074/jbc.m111.315705

Cited by 59 publications

(43 citation statements)

References 46 publications

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“…Under stress conditions, glutathione was found to be turned over rapidly with a half-life of 60 min, but surprisingly, even under un-stressed conditions glutathione was turned over with a half-life of ϳ90 min (14). The human and mouse ChaC2 proteins described are likely to participate in a similar continuous and constant, housekeeping function of glutathione degradation in mammalian cells.…”

Section: Discussionmentioning

confidence: 95%

“…With the yeast S. cerevisiae and the plant Arabidopsis thaliana also having multiple pathways for glutathione degradation (29), it is clear that glutathione degradation, which has until now been relatively poorly investigated, has a far more important role to play in glutathione homeostasis. Studies in yeast have in fact led to conclude that glutathione degradation is the key element in glutathione homeostasis (14).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is important for the cell to ensure that the levels of glutathione are tightly regulated. Glutathione degradation and turnover is an important factor in glutathione homeostasis (14). However, for several decades, only a single enzyme, ␥-glutamyltranspeptidase, was shown to be responsible for glutathione degradation, but its effects were on non-cytosolic pools of glutathione (15).…”

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confidence: 99%

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ChaC2, an Enzyme for Slow Turnover of Cytosolic Glutathione

Kaur

Gautam

Srivastava

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeGlutathione degradation plays an important role in glutathione and redox homeostasis, and thus it is imperative to understand the enzymes and the mechanisms involved in glutathione degradation in detail. We describe here ChaC2, a member of the ChaC family of ␥-glutamylcyclotransferases, as an enzyme that degrades glutathione in the cytosol of mammalian cells. ChaC2 is distinct from the previously described ChaC1, to which ChaC2 shows ϳ50% sequence identity. and ChaC2 proteins also shared the same specificity for reduced glutathione, with no activity against either ␥-glutamyl amino acids or oxidized glutathione. The ChaC2 proteins were found to be expressed constitutively in cells, unlike the tightly regulated ChaC1. Moreover, lower eukaryotes have a single member of the ChaC family that appears to be orthologous to ChaC2. In addition, we determined the crystal structure of yeast ChaC2 homologue, GCG1, at 1.34 Å resolution, which represents the first structure of the ChaC family of proteins. The catalytic site is defined by a fortuitous benzoic acid molecule bound to the crystal structure. The mechanism for binding and catalytic activity of this new enzyme of glutathione degradation, which is involved in continuous but basal turnover of cytosolic glutathione, is proposed.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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ChaC2, an Enzyme for Slow Turnover of Cytosolic Glutathione

Kaur

Gautam

Srivastava

et al. 2017

Journal of Biological Chemistry

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“…Previous findings have shown that GCL is a direct target of caspase 3 (78,79), which during apoptosis should not only prevent GSH replenishment but also contribute to GSH depletion, as GSH's half-life has been estimated to be between 2 and 5 h (18,113,207). Furthermore, the impairment of cysteine uptake during cell death induced by parkinsonian neurotoxins has also been suggested as contributing to GSH depletion (5) ( Table 1 and Fig.…”

Section: Figmentioning

confidence: 99%

Glutathione Efflux and Cell Death

Franco

Cidlowski

2012

Antioxidants & Redox Signaling

187

127

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Significance: Glutathione (GSH) depletion is a central signaling event that regulates the activation of cell death pathways. GSH depletion is often taken as a marker of oxidative stress and thus, as a consequence of its antioxidant properties scavenging reactive species of both oxygen and nitrogen (ROS/RNS). Recent Advances: There is increasing evidence demonstrating that GSH loss is an active phenomenon regulating the redox signaling events modulating cell death activation and progression. Critical Issues: In this work, we review the role of GSH depletion by its efflux, as an important event regulating alterations in the cellular redox balance during cell death independent from oxidative stress and ROS/RNS formation. We discuss the mechanisms involved in GSH efflux during cell death progression and the redox signaling events by which GSH depletion regulates the activation of the cell death machinery. Future Directions: The evidence summarized here clearly places GSH transport as a central mechanism mediating redox signaling during cell death progression. Future studies should be directed toward identifying the molecular identity of GSH transporters mediating GSH extrusion during cell death, and addressing the lack of sensitive approaches to quantify GSH efflux.

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“…Degradation of GSH is also an important determinant of its homeostasis. Initially thought to be operated in the vacuole by c-glutamyl transpeptidase (c-GT) under conditions of nitrogen starvation (55), recent data indicate that the newly discovered Dug1/Dug2 glutamine amidotransferase, which cleaves GSH at the c-glutamyl-cysteine bond (38), and Dug3, a Cys-Gly dipeptidase (39), form a complex that is responsible for all GSH-degrading activity of yeast cells under normal and stress conditions, including sulfur and nitrogen starvation and cadmium exposure (4,23). Lastly, NADPH is the major proton donor for disulfide reduction.…”

Section: Cellular Distribution Of Thiol Redox Control Componentsmentioning

confidence: 99%

Functions and Cellular Compartmentation of the Thioredoxin and Glutathione Pathways in Yeast

Toledano

Delaunay‐Moisan

Outten

et al. 2013

Antioxidants & Redox Signaling

110

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Significance: The thioredoxin (TRX) and glutathione (GSH) pathways are universally conserved thiol-reductase systems that drive an array of cellular functions involving reversible disulfide formation. Here we consider these pathways in Saccharomyces cerevisiae, focusing on their cell compartment-specific functions, as well as the mechanisms that explain extreme differences of redox states between compartments. Recent Advances: Recent work leads to a model in which the yeast TRX and GSH pathways are not redundant, in contrast to Escherichia coli. The cytosol possesses full sets of both pathways, of which the TRX pathway is dominant, while the GSH pathway acts as back up of the former. The mitochondrial matrix also possesses entire sets of both pathways, in which the GSH pathway has major role in redox control. In both compartments, GSH has also nonredox functions in iron metabolism, essential for viability. The endoplasmic reticulum (ER) and mitochondrial intermembrane space (IMS) are sites of intense thiol oxidation, but except GSH lack thiol-reductase pathways. Critical Issues: What are the thiol-redox links between compartments? Mitochondria are totally independent, and insulated from the other compartments. The cytosol is also totally independent, but also provides reducing power to the ER and IMS, possibly by ways of reduced and oxidized GSH entering and exiting these compartments. Future Directions: Identifying the mechanisms regulating fluxes of GSH and oxidized glutathione between cytosol and ER, IMS, and possibly also peroxisomes, vacuole is needed to establish the proposed model of eukaryotic thiol-redox homeostasis, which should facilitate exploration of this system in mammals and plants.

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Glutathione Degradation Is a Key Determinant of Glutathione Homeostasis

Cited by 59 publications

References 46 publications

ChaC2, an Enzyme for Slow Turnover of Cytosolic Glutathione

ChaC2, an Enzyme for Slow Turnover of Cytosolic Glutathione

Glutathione Efflux and Cell Death

Functions and Cellular Compartmentation of the Thioredoxin and Glutathione Pathways in Yeast

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