GLUTATHIONE SYNTHESIS
By Shelly C. Lu. Biochimica et Biophysica Acta, 2012
1,929 citations recorded by the source corpus.
BACKGROUND Glutathione (GSH) is present in all mammalian tissues as the most abundant non-protein thiol that defends against oxidative stress. GSH is also a key determinant of redox signaling, vital in detoxification of xenobiotics, regulates cell proliferation, apoptosis, immune function, and fibrogenesis. Biosynthesis of GSH occurs in the cytosol in a tightly regulated manner. Key determinants of GSH synthesis are the availability of the sulfur amino acid precursor, cysteine, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL), which is composed of a catalytic (GCLC) and a modifier (GCLM) subunit. The second enzyme of GSH synthesis is GSH synthetase (GS). SCOPE OF REVIEW This review summarizes key functions of GSH and focuses on factors that regulate the biosynthesis of GSH, including pathological conditions where GSH synthesis is dysregulated. MAJOR CONCLUSIONS GCL subunits and GS are regulated at multiple levels and often in a coordinated manner. Key transcription factors that regulate the expression of these genes include NF-E2 related factor 2 (Nrf2) via the antioxidant response element (ARE), AP-1, and nuclear factor kappa B (NFκB). There is increasing evidence that dysregulation of GSH synthesis contributes to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary and liver fibrosis, alcoholic liver disease, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. GENERAL SIGNIFICANCE GSH is a key antioxidant that also modulates diverse cellular processes. A better understanding of how its synthesis is regulated and dysregulated in disease states may lead to improvement in the treatment of these disorders.
Subfields: Biochemistry, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/bae7ece23d19503c940e83746abfba298c7b30b6
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Citations in the corpus
- Oxidative stress response and Nrf2 signaling in aging. (2015, neutral): “It is well established that oxidative stress or disturbance of GSH homeostasis usually causes the induction of an adaptive response that increases GSH production [143].”
- Glutathione metabolism in cancer progression and treatment resistance (2018, background): “Besides the synthetic pathway described above, cells can convert GSSG to GSH (Lu, 2013) catalyzed by GSH reductase, which requires NAD PH as a substrate and thus links NAD PH levels directly to GSH synthesis.”
- Oxidative Stress in Cancer (2020, background): “…ligase ([GCL], previously called γ-glutamylcysteine synthetase [γGCS], comprising catalytic [GCLC, or γGCSh] and modifier [GCLM, or γGCSl] subunits), and glutathione synthetase (GSS), in which GCL catalyzes the initial rate-limiting step and GSS the second and final step (Lu, 2013).”
- Antioxidant responses and cellular adjustments to oxidative stress (2015, neutral): “regulatory role on the other subunit [6].”
- Glutathione: new roles in redox signaling for an old antioxidant (2014, background): “GCL forms an unusual peptide bond between the γcarboxyl of glutamate and the amino group of cysteine using the energy provided by the hydrolysis of ATP (Lu, 2013).”
- Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal (2014, background): “The main genes regulated by 4-HNE- inducedNrf2-ARE pathway are as follows: (i) HO-1, an antioxidant protein that catalyzes the degradation of heme to biliverdin, which is then degraded to bilirubin; both biliverdin and bilirubin have antioxidant properties [227]; 4-HNE can upregulate HO-1 [217, 220,”