Glutathione synthesis

doi:10.1016/j.bbagen.2012.09.008

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1830, Issue 5, May 2013, Pages 3143-3153

https://doi.org/10.1016/j.bbagen.2012.09.008 Get rights and content

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.

Highlights

► GSH regulates antioxidant defense, growth, death, immune function, and fibrogenesis. ► GSH is synthesized via two enzymatic steps that are regulated at multiple levels. ► GSH synthesis is dysregulated in multiple human diseases.

Introduction

Glutathione (GSH) is a tripeptide, γ-L-glutamyl-L-cysteinylglycine, present in all mammalian tissues at 1–10 mM concentrations (highest concentration in liver) 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 modulates cell proliferation, apoptosis, immune function, and fibrogenesis. This review is focused on factors that determine GSH synthesis and pathologies where dysregulation in GSH synthesis may play an important role with emphasis on the liver. This is because the liver plays a central role in the interorgan GSH homeostasis [1].

Section snippets

Structure and functions of GSH

GSH exists in the thiol-reduced and disulfide-oxidized (GSSG) forms [2]. GSH is the predominant form and accounts for > 98% of total GSH [3], [4], [5]. Eukaryotic cells have three major reservoirs of GSH. Most (80–85%) of the cellular GSH are in the cytosol; 10–15% is in the mitochondria and a small percentage is in the endoplasmic reticulum [6], [7], [8]. Rat liver cytosolic GSH turns over rapidly with a half-life of 2–3 h. The structure of GSH is unique in that the peptide bond linking

Synthesis of GSH

The synthesis of GSH from its constituent amino acids involves two ATP-requiring enzymatic steps: formation of γ-glutamylcysteine from glutamate and cysteine and formation of GSH from γ-glutamylcysteine and glycine (Fig. 1). The first step of GSH biosynthesis is rate limiting and catalyzed by GCL (EC 6.3.2.2; formerly γ-glutamylcysteine synthetase), which is composed of a heavy or catalytic (GCLC, Mr ~ 73 kDa) and a light or modifier (GCLM, Mr ~ 31 kDa) subunit, which are encoded by different genes

Regulation of glutamate-cysteine ligase (GCL)

Changes in GCL activity can result from regulation at multiple levels affecting only GCLC or both GCLC and GCLM.

Regulation of GSH synthase (GS)

GS has received relatively little attention in the field of GSH biosynthesis. GS is composed of two identical subunits and is not subject to feedback inhibition by GSH [48]. GS deficiency in humans can result in dramatic metabolic consequences because the accumulated γ-glutamylcysteine is converted to 5-oxoproline, which can cause severe metabolic acidosis, hemolytic anemia and central nervous system damage [137], [138]. Choi et al. described decreased hepatic GSH levels, which correlated with

Dysregulation of GSH synthesis

There is accumulating data that reduced GSH levels occur in many human diseases and they contribute to worsening of the condition [4]. While oxidative injury plays a dominant role in GSH depletion in many of these disorders, some are causally related to reduced expression of GSH synthetic enzymes [13]. In the most severe cases, polymorphisms of GCLC and/or GCLM that result in significantly reduced GCL expression and activity can present with severe phenotype including hemolytic anemia,

Concluding remarks

Up until recently, most of the literature on GSH synthesis has focused on understanding how the enzymes are regulated transcriptionally and post-transcriptionally. There are now increasing evidence that show dysregulation of GSH synthesis in multiple conditions, such as aging, diabetes, pulmonary fibrosis, hepatic fibrosis, and alcoholic and cholestatic liver injuries. Some of these have been confirmed to occur also in humans. GCLC and GCLM polymorphisms have also gained attention as another

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^☆: This article is part of a Special Issue entitled Cellular functions of glutathione.

^☆☆: This work was supported by NIH grant R01DK092407.

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ReviewGlutathione synthesis☆,☆☆

Abstract

Background

Scope of review

Major conclusions

General significance

Highlights

Introduction

Section snippets

Structure and functions of GSH

Synthesis of GSH

Regulation of glutamate-cysteine ligase (GCL)

Regulation of GSH synthase (GS)

Dysregulation of GSH synthesis

Concluding remarks

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Review
Glutathione synthesis☆,☆☆