Glutathione; Metabolism and function via the γ-glutamyl cycle

doi:10.1016/0024-3205(74)90206-9

Life Sciences

Volume 15, Issue 2, 15 July 1974, Pages 177-190

https://doi.org/10.1016/0024-3205(74)90206-9 Get rights and content

Abstract

The intracellular synthesis of glutathione and the breakdown of this ubiquitous tripeptide are linked by a series of enzyme-catalyzed reactions which have been collectively termined the γ-glutamyl cycle. Earlier work on the γ-glutamyl cycle has been reviewed (1,2); this minireview summarizes the background of this area, the major previous findings, recent developments, and evidence that the γ-glutamyl cycle functions in amino acid transport.

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Rat liver glutathione S-transferase-catalyzed conjugation of glutathione to the endogenous epoxides of oleic acid and cholesterol
2022, Analytical Biochemistry
Citation Excerpt :
Cytosolic and microsomal epoxide hydrolases (EH) are detoxifying enzymes that specifically metabolize epoxides [25]. GSH is formed in the γ-glutamyl cycle (Fig. S7) and is provided as a cofactor/substrate for various reactions including those catalyzed by GST [26,27]. Several diseases are associated with specific enzyme deficiencies of the γ-glutamyl cycle [28].
cis-9,10-Epoxy-octadecanoic acid (oleic acid epoxide, OAE) and 5α,6α-epoxy-cholesterol (ChE) are endogenous epoxides. Unlike other epoxides, the oxirane groups of OAE and ChE are relatively stable against nucleophiles. OAE lacks toxicity and mutagenicity, while ChE is considered harmful, mutagenic and cancerogenic to animals. In humans, ChE is associated with cancer. The metabolism of OAE and ChE includes hydrolysis by cytosolic and microsomal hydrolases to their diols and glutathione (GSH) conjugation by GSH S-transferases (GST) to form the GSH conjugates (R-SG; R, residue). The GST-catalyzed GSH conjugation of OAE and ChE is poorly investigated. This article reports on the GSH conjugation of OAE, its methyl ester (OAEMe) and of ChE by rat liver homogenate GST. The GSH conjugates of OAE, OAEMe and ChE, i.e., OAE-SG, OAEMe-SG and ChE-SG, respectively, were determined by pre-column derivatization with o-phthaldialdehyde (OPA)/2-mercaptoethanol, high-performance liquid chromatography (HPLC) and fluorescence detection. Complex biphasic kinetics were observed with substrate inhibition of GST activity by OAE, OAEMe and ChE, an optimum pH of about 8.3 for OAE, and no measurable chemical GSH conjugation, underlying the importance of GST for the biotransformation of these epoxides. The results confirm the substrate concentration-dependent kinetic mechanism of GST isoforms first reported by William B. Jakoby (J. Biol. Chem. 1974) for exogenous electrophiles including the epoxide 1,2-epoxy-3-(p-nitrophenoxy)propane and the organic nitrates. This mechanism allows for maximal GST activity that can be achieved under given concentrations of GSH, epoxides and other electrophiles.
The anti-aging effect of Scutellaria baicalensis Georgi flowers extract by regulating the glutamine-glutamate metabolic pathway in D-galactose induced aging rats
2020, Experimental Gerontology
Citation Excerpt :
The GSH synthesis involves the combination of cysteine with glutamate to produce γ-glutamylcysteine catalyzed by the enzyme GCL. The next step involves the enzyme glutathione synthetase (GSS), responsible for adding glycine to the dipeptide to produce GSH (Meister, 1974). Studies have found that overexpression of GSS doesn't increase GSH activity, while overexpression of GCL can increase GSH activity.
Scutellaria baicalensis Georgi flowers is rich in flavonoids resources but not effectively exploited. This study aimed to investigate the anti-aging effects and potential mechanism of Scutellaria baicalensis Georgi flowers extract (SFE). The chemical components of the SFE were analyzed by UPLC-MS and the anti-aging effects of SFE were investigated in d-galactose (d-gal) induced aging rats by behavior examination and biochemical indexes, and the potential anti-aging mechanism of SFE were explored by ¹H NMR-based liver metabolomics. Chemical composition research showed that 19 flavonoids were identified in SFE, and pharmacological research showed that SFE could significantly ameliorate spatial learning and memory ability. SFE could significantly regulate malondialdehyde (MDA), superoxide dismutase (SOD) and advanced glycation end products (AGEs). It also ameliorated the pathological abnormalities in liver. Additionally, anti-aging mechanism of SFE showed that total of 10 potential biomarkers were found by metabolomics techniques, which involved in 6 metabolic pathways. Among them, SFE could significantly increased the levels of d-glutamine and d-glutamate. Furthermore, the levels of glutamine and glutamate, and the levels of the key amino acids, enzymes and final product in the synthesis process of glutathione (GSH) were quantitatively determined in the liver by commercial kits and enzyme-linked immunosorbent assay. These results indicated that regulation of the glutamine-glutamate metabolic pathway is involved in the anti-aging effect of SFE in d-gal induced aging rats.
Ras Downstream Effector GGCT Alleviates Oncogenic Stress
2019, iScience
Citation Excerpt :
Extracellular GSH can be hydrolyzed by membrane-bound γ-glutamyl transpeptidase (GGT) to cysteinylglycine and γ-glutamyl-amino acid dipeptide (Anderson, 1998; Meister, 1988). In the cytoplasm, γ-glutamyl cyclotransferase cleaves the γ-glutamyl-amino acid to give 5-oxoproline and amino acid (Meister, 1974). However, the function of GGCT (C7orf24) in GSH homeostasis is still unknown.
How cells adapt to oncogenic transformation-associated cellular stress and become fully transformed is still unknown. Here we identified a novel GGCT-regulated glutathione (GSH)-reactive oxygen species (ROS) metabolic pathway in oncogenic stress alleviation. We identified GGCT as a target of oncogenic Ras and that it is required for oncogenic Ras-induced primary mouse cell proliferation and transformation and in vivo lung cancer formation in the LSL-Kras G12D mouse model. However, GGCT deficiency is compatible with normal mouse development, suggesting that GGCT can be a cancer-specific therapeutic target. Genetically amplified GGCT locus further supports the oncogenic driving function of GGCT. In summary, our study not only identifies an oncogenic function of GGCT but also identifies a novel regulator of GSH metabolism, with implications for further understanding of oncogenic stress and cancer treatment.
Temporal changes in glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response of THP-1 macrophages
2017, Free Radical Biology and Medicine
Citation Excerpt :
The de novo GSH biosynthesis is mainly regulated through glutamate cysteine ligase (GCL), the rate-limiting enzyme in the biosynthesis reaction. GCL activity is determined by several factors including the absolute protein levels of both its catalytic subunit (GCLC) and modifier subunit (GCLM) [15,16], the ratio of GCLC/GCLM [17], and the feedback inhibition of GCL by GSH itself [18]. Studies from past decades have demonstrated that the expression of both GCLC and GCLM subunits could be induced in response to oxidative stress, through nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling [16,19–22].
How macrophages maintain redox homeostasis in the inflammatory process, in which a large amount of oxidants are produced, remains elusive. In this study, we investigated the temporal changes in the intracellular glutathione (GSH), the master antioxidant, and the expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH biosynthesis, in the inflammatory response of human macrophages (THP1 cells) to lipopolysaccharide. Intracellular GSH concentration was decreased significantly in the early phase (~6 h) of LPS exposure, and then gradually went back to the basal level in the late phase (9–24 h). The expression level of the catalytic subunit of GCL (GCLC) followed a similar pattern of change as GSH: its mRNA and protein levels were reduced in the early phase and then back to basal level in the late phase. In contrast, the expression of the modifier subunit of GCL (GCLM) was significantly increased in the phase of LPS exposure. Activation Nrf2, the transcription factor involved in the induction of both GCLC and GCLM, occurred at as early as 3 h after LPS exposure; whereas the activation of NF-κB occurred at as early as 30 min. Inhibition of NF-κB signaling with SN50 prevented the decrease of GCLC and inhibited Nrf2 activation in response to LPS. These data demonstrate time-dependent changes in the expression of GCL and Nrf2 signaling during the inflammatory response, and that the regulation of GCLC and GCLM might be through different pathways in this process.
Enlightening the Mechanism of Ferroptosis in Epileptic Heart
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Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity
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MinireviewGlutathione; Metabolism and function via the γ-glutamyl cycle

Abstract

The Enzymes (3rd edition)

Clin. Chim. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Neurochem.

Biochem. Pharmacol.

J. Natl. Cancer Inst.

Science

Glutathione

The γ-Glutamyl Transpeptidation Reaction

Nature

Symposium on Glutathione

Amino Acid Metabolism with Special Reference to Peptide Bond Transfer

Biol. Bull.

Acta Biochimica Polonica

Biochem. Zeit.

Arch. Immunol. Ther. Exp.

Biochemistry of the Amino Acids (2nd Edition)

Arch. Immunol. Therap. Exp.

Biochemistry

Nature

Nature

J. Histochem. Cytochem.

Acta Histochem.

Acta Histochem.

Nature

Biochem. J.

Minireview
Glutathione; Metabolism and function via the γ-glutamyl cycle