Glutathione Degradation

Bachhawat, Anand K.; Kaur, Amandeep

doi:10.1089/ars.2017.7136

Cited by 90 publications

(81 citation statements)

References 149 publications

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“…This is especially so in the light of the recent data that has emerged on glutathione degradation. A new cycle becomes apparent with these new discoveries and we refer to this as the “Glutathione cycle” (Fig. ).…”

Section: The Proposed “Glutathione Cycle”mentioning

confidence: 99%

“…Despite the elegance of the cycle, the proposed function of the cycle in amino acid transport has subsequently proved incorrect. Furthermore, new understanding on the transport of amino acids and glutathione, identification and characterization of the genes for the enzymes that were previously unidentified in the cycle, identification of γ‐glutamyl acting enzymes unlinked to glutathione metabolism, as well as discoveries of new enzymes for the degradation of glutathione, has revealed that the steps relating to the degradation of glutathione, and downstream of the initiation of degradation are now quite different from what was originally proposed . Surprisingly, the sequence of reactions and even the pictorial representation of the cycle continue to persist in many textbooks of biochemistry as well as metabolic pathway databases such as Metacyc.…”

Section: Introductionmentioning

confidence: 99%

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The glutathione cycle: Glutathione metabolism beyond the γ‐glutamyl cycle

2018

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Glutathione was discovered in 1888, over 125 years ago. Since then, our understanding of various functions and metabolism of this important molecule has grown over these years. But it is only now, in the last decade, that a somewhat complete picture of its metabolism has emerged. Glutathione metabolism has till now been largely depicted and understood by the γ-glutamyl cycle that was proposed in 1970. However, new findings and knowledge particularly on the transport and degradation of glutathione have revealed that many aspects of the γ-glutamyl cycle are incorrect. Despite this, an integrated critical analysis of the cycle has never been undertaken and this has led to the cycle and its errors perpetuating in the literature. This review takes a careful look at the γ-glutamyl cycle and its shortcomings and presents a "glutathione cycle" that captures the current understanding of glutathione metabolism. © 2018 IUBMB Life, 70(7):585-592, 2018.

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Section: The Proposed “Glutathione Cycle”mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The glutathione cycle: Glutathione metabolism beyond the γ‐glutamyl cycle

2018

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“…GSH homeostasis is balanced by GSH biosynthesis, transport and efflux of GSH, GSH-acting enzymes, and GSH degradation [6]. Although the contribution of GSH biosynthesis has been well studied, the GSH degradation pathway, which involves the initial cleavage of GSH, remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

et al. 2019

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Glutathione (GSH) degradation plays an essential role in GSH homeostasis, which regulates cell survival, especially in cancer cells. Among human GSH degradation enzymes, the ChaC2 enzyme acts on GSH to form 5-l-oxoproline and Cys-Gly specifically in the cytosol. Here, we report the crystal structures of ChaC2 in two different conformations and compare the structural features with other known γ-glutamylcyclotransferase enzymes. The unique flexible loop of ChaC2 seems to function as a gate to achieve specificity for GSH binding and regulate the constant GSH degradation rate. Structural and biochemical analyses of ChaC2 revealed that Glu74 and Glu83 play crucial roles in directing the conformation of the enzyme and in modulating the enzyme activity. Based on a docking study of GSH to ChaC2 and binding assays, we propose a substrate-binding mode and catalytic mechanism. We also found that overexpression of ChaC2, but not mutants that inhibit activity of ChaC2, significantly promoted breast cancer cell proliferation, suggesting that the GSH degradation by ChaC2 affects the growth of breast cancer cells. Our structural and functional analyses of ChaC2 will contribute to the development of inhibitors for the ChaC family, which could effectively regulate the progression of GSH degradation-related cancers.

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“…GSH biosynthesis and degradation are together referred to as the γ‐glutamyl cycle (Fig. S1), necessary for GSH homeostasis (Bachhawat & Kaur, ). GSH turnover in Arabidopsis is known to be rapid (Ohkama‐Ohtsu et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Arabidopsis γ‐glutamylcyclotransferase affects glutathione content and root system architecture during sulfur starvation

et al. 2018

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c-Glutamylcyclotransferase initiates glutathione degradation to component amino acids L-glutamate, L-cysteine and L-glycine. The enzyme is encoded by three genes in Arabidopsis thaliana, one of which (GGCT2;1) is transcriptionally upregulated by starvation for the essential macronutrient sulfur (S). Regulation by S-starvation suggests that GGCT2;1 mobilizes L-cysteine from glutathione when there is insufficient sulfate for de novo L-cysteine synthesis.The response of wild-type seedlings to S-starvation was compared to ggct2;1 null mutants. S-starvation causes glutathione depletion in S-starved wild-type seedlings, but higher glutathione is maintained in the primary root tip than in other seedling tissues. Although GGCT2;1 is induced throughout seedlings, its expression is concentrated in the primary root tip where it activates the c-glutamyl cycle. S-starved wild-type plants also produce longer primary roots, and lateral root growth is suppressed. While glutathione is also rapidly depleted in ggct2;1 null seedlings, much higher glutathione is maintained in the primary root tip compared to the wild-type. S-starved ggct2;1 primary roots grow longer than the wild-type, and lateral root growth is not suppressed.These results point to a role for GGCT2;1 in S-starvation-response changes to root system architecture through activity of the c-glutamyl cycle in the primary root tip. L-Cysteine mobilization from glutathione is not solely a function of GGCT2;1.

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Glutathione Degradation

Cited by 90 publications

References 149 publications

The glutathione cycle: Glutathione metabolism beyond the γ‐glutamyl cycle

The glutathione cycle: Glutathione metabolism beyond the γ‐glutamyl cycle

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

Arabidopsis γ‐glutamylcyclotransferase affects glutathione content and root system architecture during sulfur starvation

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