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Review
, 1830 (5), 3143-53

Glutathione Synthesis

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Review

Glutathione Synthesis

Shelly C Lu. Biochim Biophys Acta.

Abstract

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, and 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. This article is part of a Special Issue entitled Cellular functions of glutathione.

Figures

Fig. 1
Fig. 1. GSH synthesis
Synthesis of GSH occurs via a two-step ATP-requiring enzymatic process. The first step is catalyzed by glutamate-cysteine ligase (GCL), which is composed of catalytic and modifier subunits (GCLC and GCLM). This step conjugates cysteine with glutamate, generating γ-glutamylcysteine. The second step is catalyzed by GSH synthase, which adds glycine to γ-glutamylcysteine to form γ-glutamylcysteinylglycine or GSH. GSH exerts a negative feedback inhibition on GCL.
Fig. 2
Fig. 2. Antioxidant function of GSH
Aerobic metabolism generates hydrogen peroxide (H2O2), which can be metabolized by GSH peroxidase (GPx) in the cytosol and mitochondria, and by catalase in the peroxisome. GSSG can be reduced back to GSH by GSSG reductase (GR) at the expense of NADPH, thereby forming a redox cycle. Organic peroxides (ROOH) can be reduced by either GPx or GSH S-transferase (GST). GSH also plays a key role in protein redox signaling. During oxidative stress, protein cysteine residues can be oxidized to sulfenic acid (Prot-SOH), which can react with GSH to form protein mixed disulfides Prot-SSG (glutathionylation), which in turn can be reduced back to Prot-SH via glutaredoxin (Grx) or sulfiredoxin (Srx). This is a mechanism to protect sensitive protein thiols from irreversible oxidation and may also serve to prevent loss of GSH under oxidative conditions. The ability of the cell to reduce GSSG to GSH may be overcome during severe oxidative injury, leading to an accumulation of GSSG. To prevent a shift in the redox equilibrium, GSSG can either be actively transported out of the cell or react with a protein sulfhydryl (Prot-SH) to form a mixed disulfide (Prot-SSG).
Fig. 3
Fig. 3. GSH is a continuous source of cysteine via the γ-glutamyl cycle
GSH is transported out of the cell where the ecto-enzyme γ-glutamylpeptidase (GGT) transfers the γ-glutamyl moiety of GSH to an amino acid (the best acceptor being cystine), forming γ-glutamyl amino acid and cysteinylglycine. The γ-glutamyl amino acid can then be transported back into the cell and once inside, the γ-glutamyl amino acid can be further metabolized to release the amino acid and 5-oxoproline, which can be converted to glutamate and reincorporated into GSH. Cysteinylglycine is broken down by dipeptidase (DP) to generate cysteine and glycine, which are also transported back into the cell to be reincorporated into GSH. Most of the cysteine taken up is incorporated into GSH while the rest is incorporated into newly synthesized proteins and/or broken down into sulfate and taurine.
Fig. 4
Fig. 4. Hepatic methionine metabolism
Liver plays a central role in methionine catabolism as up to half of the daily intake of methionine is catabolized to S-adenosylmethionine (SAMe) in the liver in a reaction catalyzed by methionine adenosyltransferase (MAT). SAMe is the principal biological methyl donor and donates its methyl group to a large variety of acceptor molecules in reactions catalyzed by methyltransferases (MTs). S-adenosylhomocysteine (SAH), generated as a result of transmethylation, is a potent inhibitor of all transmethylation reactions. To prevent SAH accumulation, it is hydrolyzed to homocysteine and adenosine is through a reversible reaction catalyzed by SAH hydrolase, whose thermodynamics favors biosynthesis rather than hydrolysis. Prompt removal of homocysteine and adenosine ensures SAH is hydrolyzed. Homcysteine can be remethylated to form methionine via methionine synthase (MS), which requires folate and vitamin B12 and betaine homocysteine methyltransferase (BHMT), which requires betaine. In hepatocytes, homocysteine can also undergo conversion to cysteine (Cys) via the transsulfuration pathway, a two-step enzymatic process catalyzed by cystathionine β-synthase (CBS) and cystathionase, both requiring vitamin B6. Liver has the highest activity of transsulfuration, which allows methionine and SAMe to be effectively utilized as GSH precursor.

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