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evolution
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in eukaryotes gamma -glutamylcysteine synthetase and glutathione synthetase, EC 6.3.2.3, activities are encoded by two distinct enzymes In some prokaryotes, such as Escherichia coli and Vibrio cholerae, separate enzymes exist for these two reactions. However, in some prokaryotes, such as Streptococcus agalactiae, Pasteurella multicoda and Listeria monocytogenes, both of these activities are encoded by a single bifunctional enzyme, GshF. Evolution of gamma-GCS has occurred by convergent evolution in three different lineages with no significant sequence similarities between the lineages, the Escherichia coli enzyme belongs to lineage I
evolution
Synechocystis GCL is part of the plant-like GCL family, the Synechocystis enzyme lacks the redox regulation associated with the plant enzymes and functions as a monomeric protein, indicating that evolution of redox regulation occurs later in the green lineage
evolution
Gsh1 belongs to the eu-GC superfamily
evolution
the enzyme encoded by GSH1 belongs to the eu-GC superfamily
malfunction
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erythrocytes from gclm-/- mice show greatly reduced intracellular glutathione. Prolonged incubation results in complete lysis of gclm-/- erythrocytes, which can be reversed by exogenous delivery of the antioxidant Trolox. Phenylhydrazine-induced oxidative stress in glcm-/- causes dramatically increased hemolysis, markedly larger accumulations of injured erythrocytes in the spleen, erythrocyte-derived pigment hemosiderin in kidney tubules, and diminished kidney function compared to wild-type mice, phenotype, overview. Regulatory subunit GCLM-deficient erythrocytes are more prone to Ca2+-dependent suicidal cell death ex vivo. Without additional oxidative stress, the mutant animals are able to survive by slightly ramping up their generation of new erythrocytes
malfunction
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using GCLC knockout murine embryonic fibroblasts, addition of cysteine to catalytic subunit GCLC null cells results in a marked decrease in regulatory subunit GCLM mRNA levels despite the absence of GSH
malfunction
a gene disruptant mutant without GSH1 gene cannot grow in the absence of GSH
malfunction
GSH can be depleted through the specific downregulation of the GCL levels by hammerhead ribozyme
malfunction
in patients with systemic lupus erythematosus (SLE), the levels of enzyme GCL activity and reduced glutathione (GSH) decrease, while thioredoxin (TRX) and oxidized glutathione (GSSG) levels increase when compared with those in the healthy controls. GSH concentrations and GCL activity levels negatively correlate with the SLE disease activity index and erythrocyte sedimentation rate. Patients with SLE and nephritis have lower levels of GSH and GCL activity and higher levels of TRX and GSSG compared with those in SLE patients without nephritis. Insufficient levels of GSH and GCL activity in PBMCs may contribute to the pathogenesis of SLE. A negative association of GSH levels with T-lymphocyte and CD4+ and CD8+ lymphocyte subset apoptosis, and intracellular activated caspase?3 may supports the role of GSH in the alteration of apoptosis of T lymphocytes in the SLE disease state. GSH is involved in the depletion of CD4+ T lymphocytes in patients with SLE
malfunction
overexpression of subunit Gclc-X2 leads to upregulation of the proteins Abcf1, Fkbp4, and Eif3h, as well as to downregulation of protein Lamb1. There is no significant difference in growth rate during exponential phase at 32C between Gclm+ or Gclc-X2+ populations and the wild-type population. A higher cell proliferation observed in the Gclc overexpressing population. Gclc-X2 but not Gclm overexpression increases Gcl activity
malfunction
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a gene disruptant mutant without GSH1 gene cannot grow in the absence of GSH
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metabolism
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the regulation of GCL, especially the catalytic subunit, with stress may be compromised in aging muscles. In aging muscles with 14 days of hind-limb unloading, failure to maintain the accelerated GCL catalytic subunit production and GCL activity, are associated with the GSH depletion
metabolism
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biosynthesis of GSH occurs by two sequential ATP-dependent enzymatic steps. The first enzyme, gamma -glutamylcysteine synthetase ligates glutamate and cysteine to yield gamma -glutamylcysteine. Glutathione synthetase, EC 6.3.2.3, the second enzyme, then catalyses the addition of glycine to yield glutathione
metabolism
certain carotenoids induce the Gcl mRNA expression in RAW264 cells and subsequently the GCL protein expression, which concomitantly enhances the intracellular GSH level, in a JNK pathway-related manner
metabolism
glutamate cysteine ligase (GCL) catalyzes the first and rate-limiting step of glutathione, GSH, biosynthesis. The associations between GSH levels and GCL activity with demographic characteristics, clinical manifestations and laboratory parameters in peripheral blood mononuclear cells (PBMCs) are analyzed, overview
metabolism
glutamate-cysteine ligase is one of the two enzymes involved in the synthesis of glutathione (GSH). This tripeptide is synthesized by two consecutive enzymatic reactions. Ligation of glutamate and cysteine,the rate-limiting step of GSH de novo synthesis, is catalyzed by glutamate-cysteine ligase. The following addition of glycine to the dipeptide is catalyzed by glutathione synthetase, EC 6.3.2.3
metabolism
the bifunctional enzyme gshF catalyzes both steps of glutathione biosynthesis in Streptococcus thermophilus
metabolism
the enzyme catalyses the first step of glutathione biosynthesis by forming gamma-glutamyl-cysteine from glutamate and cysteine in an ATP-dependent reaction. Formation of gamma-glutamyl-cysteine is not the rate-limiting step of glutathione biosynthesis in Pseudoalteromonas haloplanktis
metabolism
the enzyme catalyzes the first step in the glutathione biosynthesis
metabolism
the enzyme catalyzes the first step of ATP-dependent glutathione biosynthesis from L-glutamate and L-cysteine
metabolism
the enzyme catalyzes the first step of ATP-dependent glutathione biosynthesis from L-glutamate and L-cysteine. GSH production occurs through two mechanisms: de novo synthesis and GSSG recycling. De novo synthesis occurs in a two-step reaction catalyzed by the two separate enzymes, glutamate cysteine ligase and glutathione synthetase, EC 6.3.2.3
metabolism
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the bifunctional enzyme gshF catalyzes both steps of glutathione biosynthesis in Streptococcus thermophilus
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metabolism
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the enzyme catalyzes the first step of ATP-dependent glutathione biosynthesis from L-glutamate and L-cysteine
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metabolism
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the enzyme catalyzes the first step of ATP-dependent glutathione biosynthesis from L-glutamate and L-cysteine. GSH production occurs through two mechanisms: de novo synthesis and GSSG recycling. De novo synthesis occurs in a two-step reaction catalyzed by the two separate enzymes, glutamate cysteine ligase and glutathione synthetase, EC 6.3.2.3
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metabolism
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the enzyme catalyses the first step of glutathione biosynthesis by forming gamma-glutamyl-cysteine from glutamate and cysteine in an ATP-dependent reaction. Formation of gamma-glutamyl-cysteine is not the rate-limiting step of glutathione biosynthesis in Pseudoalteromonas haloplanktis
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physiological function
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generation of GSH1 null mutants in Leishmania infantum. Removal of even a single wild-type allelic copy of GSH1 invariably leads to the generation of an extra copy of GSH1, maintaining two intact wild-type alleles. By first supplementing the parasites with a rescue plasmid, both a single and null chromosomal GSH1 mutant can be obtained. Parasites with one intact GSH1 chromosomal allele lose the rescuing plasmid but not the double knockout, when grown in the absence of antibiotic, indicating the essentiality of the GSH1 gene. Heterozygous mutants with one allele inactivated transcribe less GSH1 mRNA and synthesize less glutathione and trypanothione. These mutants are more susceptible to oxidative stresses in vitro as promastigotes and show decreased survival inside activated macrophages producing reactive oxygen or nitrogen species. These mutants show a significant decreased survival in the presence of antimony
physiological function
in a strain lacking GshA activity, diamide, a thiol-specific oxidant, significantly inhibits the growth of cells in comparison to those of the wild type. In contrast, 1.0 mM paraquat, 0.1 mM t-butyl hydroperoxide, 0.5 mM hydrogen peroxide, and 0.01 mM menadione have a much less pronounced effect on growth
physiological function
knockdown of gamma-glutamylcysteine synthetase heavy chain subunit by an adenovirus vector with short hairpin RNA against GCSh. Three days infection of GCSh-shRNA and CYP3A4 simultaneously with H4IIE cells decreases the intracellular GSH level by 50-60% without affecting the expression level of CYP3A4. Using this cell-based system sensitive to the cytotoxicity of reactive metabolites, drugs known for their hepatotoxicity are evaluated. Troglitazone, flutamide, and acetaminophen cause significant decreases of cell viability in CYP3A4/GCSh-shRNA group compared to the other groups such as GFP, CYP3A4, GFP/GCSh-shRNA, indicating that reactive metabolites produced by CYP3A4 and subsequently conjugated by GSH are involved in the cytotoxicity
physiological function
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mice lacking the glutamate-cysteine ligase modifier subunit show an increase in myocardial ischaemia-reperfusion injury and apoptosis in ischaemic myocardium. A decrease in mitochondrial glutathione levels in ischaemic myocardium is more pronounced in mice lacking the glutamate-cysteine ligase modifier subunit than in control. The ESR signal intensity of the dimethyl-1-pyrroline-N-oxide-hydroxyl radical adducts in ischaemic myocardium is higher in mice lacking the glutamate-cysteine ligase modifier subunit than in control. Hypoxia-reoxygenation induces greater mitochondrial damage in cultured cardiomyocytes from mice lacking the glutamate-cysteine ligase modifier subunit
physiological function
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model to explain adenosine triphosphate depletion during cystinosis. In the absence of cysteine, enzyme gamma-glutamyl cysteine synthetase forms 5-oxoproline, and the 5-oxoproline is converted into glutamate by the ATP-dependant enzyme, 5-oxoprolinase. Thus, in cysteine-limiting conditions, glutamate is cycled back into glutamate via 5-oxoproline at the cost of two ATP molecules without production of glutathione and this is the cause of the decreased levels of glutathione synthesis, as well as the ATP depletion observed in these cells. The model is also compatible with the differences seen in the human patients and the mouse model of cystinosis, where renal failure is not observed
physiological function
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the high resistance of MYCN-amplified neuroblastoma cells against oxidative damage can be accounted for by their greater expression of both the mRNA and protein of the catalytic subunit of glutamate-cysteine ligase, the rate-limiting step in GSH biosynthesis. MYCN directly binds to an E-box containing GCL catalytic subunit promoter and over-expression of MYCN in MYCN-non-amplified cells stimulates GCL catalytic subunit expression and provides resistance to oxidative damage. Knock-down of MYCN in MYCN-amplified cells decreases GCL catalytic subunit expression and sensitizes them to oxidative damage. GCL catalytic subunit knock-down enhances the vulnerability of MYCN-amplified cells to oxidative damage
physiological function
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transfection of COV-434 granulosa tumour cell with vectors designed for the constitutive expression of Gcl catalytic subunit, Gcl modifier subunit, or both Gcl catalytic subunit and Gcl modifier subunit. GCL protein and enzymatic activity and total GSH levels are significantly increased in the GCL subunit-transfected cells. GCL-transfected cells are resistant to cell killing by treatment with hydrogen peroxide compared to control cells. In all the GCL subunit-transfected cell lines cell viability declines less than in control 1-8 h after 0.5 mM hydrogen peroxide treatment. In cells irradiated with 0, 1 or 5 Gy of g-rays, there is a dose-dependent increase in reactive oxygen species within 30 min in all cell lines, this effect is significantly attenuated in Gcl-transfected cells. Apoptosis is significantly decreased in irradiated Gclc-transfected cells compared to irradiated control cells
physiological function
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fibroblast growth factor 9 upregulates gamma-GCS and HO-1 expression to protect cortical and dopaminergic neurons from 1-methyl-4-phenylpyridinium-induced oxidative insult. Inhibition of gamma-GCS or HO-1 prevents the inhibitory effect of fibroblast growth factor 9 on 1-methyl-4-phenylpyridinium-induced H2O2 production and death in mesencephalic dopaminergic and cortical neurons. In the absence of 1-methyl-4-phenylpyridinium, the fibroblast growth factor 9-induced H2O2 reduction is blocked by HO-1 inhibitors, but not by gamma-GCS inhibitors
physiological function
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expression of both glutamate-cysteine ligase catalytic and modifier subunit is mediated by the GCN2/ATF4 stress response pathway. Regulation of modifier subunit GCLM expression may be mediated by changes in the abundance of mRNA stabilizing or destabilizing proteins. Upregulation of GCLM levels in response to low cysteine levels may serve to protect the cell in the face of a future stress requiring GSH as an antioxidant or conjugating/detoxifying agent
physiological function
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expression of both glutamate-cysteine ligase catalytic and modifier subunit is mediated by the GCN2/ATF4 stress response pathway. Regulation of modifier subunit GCLM expression may be mediated by changes in the abundance of mRNA stabilizing or destabilizing proteins. Upregulation of GCLM levels in response to low cysteine levels may serve to protect the cell in the face of a future stress requiring GSH as an antioxidant or conjugating/detoxifying agent
physiological function
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expression of both glutamate-cysteine ligase catalytic and modifier subunit is mediated by the GCN2/ATF4 stress response pathway. Regulation of modifier subunit GCLM expression may be mediated by changes in the abundance of mRNA stabilizing or destabilizing proteins. Upregulation of GCLM levels in response to low cysteine levels may serve to protect the cell in the face of a future stress requiring GSH as an antioxidant or conjugating/detoxifying agent
physiological function
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gamma-GCS is rate-limiting catalyzing the regulated step of GSH biosynthesis, being both transcriptionally and post-translationally regulated, post-translational regulation of the gamma-GCS enzyme by the redox environment
physiological function
glutathione biosynthesis catalysed by glutamate-cysteine ligase and glutathione synthetase, EC 6.3.2.3, is essential for maintaining redox homoeostasis and protection against oxidative damage in diverse eukaroytes and bacteria
physiological function
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the enzyme is rate-limiting for glutathione synthesis
physiological function
gamma-glutamylcysteine synthetase (gamma-ECS) is a key enzyme in the biosynthesis pathway of glutathione (GSH), the precursor of phytochelatins. The overexpression of the bacterial gamma-glutamylcysteine synthetase in Populus tremula x Populus alba mediates changes in cadmium influx, allocation and detoxification in poplar, analysis of net Cd2+ influx in association with H+/Ca2+, Cd tolerance, and the underlying molecular and physiological mechanisms, overview. GSH-mediated induction of the transcription of genes involved in Cd2+ transport and detoxification
physiological function
glutathione (GSH) is synthesized by a two-step enzyme reaction. In the first step, L-cysteine is ligated to the gamma carboxyl group of L-glutamic acid by glutamate-cysteine-ligase (GCL, EC 6.3.2.2), and in the second step L-glycine is bound to gamma-glutamylcysteine by glutathione synthase (EC 6.3.2.3). The first step is the ratelimiting step. Compared with the holoenzyme, the catalytic GCLc monomer shows lower enzymatic activity but higher sensitivity to feedback inhibition by GSH. Involvement of GCL activity in the increase in the intracellular GSH level induced by beta-carotene
physiological function
GSH is an essential thiol antioxidant produced in the cytosol of all cells and plays a key role in protecting against oxidative stress by neutralising free radicals and reactive oxygen species (ROS). The decline in GSH has been associated with changes in the expression and activity of the rate-limiting enzyme glutamate cysteine ligase (GCL), which produces the intermediate dipeptide gamma-glutamylcysteine. The molecular mechanisms that affect these age-related changes and the complexity of GCL regulation are analyzed. Impairment of the transcriptional activity of Nrf2 contributes to GCL dysregulation in aged rats
physiological function
GSH is synthesized de novo in a two-step process catalyzed by glutamate cysteine ligase (GCL, EC 6.3.2.2), and glutathione synthetase (GS, EC 6.3.2.3). GCL catalyzes the first and rate-limiting step, in which glutamate is ligated with cysteine to form gamma-glutamylcysteine (gamma-GC), which is rapidly linked to glycine to form GSH via the action of glutathione synthetase. Increased expression and enzymatic activity of enzyme GCL is closely associated with renal cell carcinoma (RCC) suggesting an important role for glutathione in the pathogenesis of RCC
physiological function
the bifunctional GSH synthetase catalyzes two steps in GSH synthesis, which are usually catalyzed through L-glutamate L-cysteine ligase (gamma-GCS) and L-glutathione synthetase (GS)
physiological function
the enzyme catalyses the synthesis of gamma-glutamylcysteine, a precursor of glutathione (GSH). GSH is an important intracellular molecule that protects cells against endogenous and exogenous oxidative stress, and plays a critical role in maintaining cellular redox homeostasis
physiological function
the enzyme catalyzes the first rate-limiting step in the biosynthesis of glutathione. Glutathione (GSH) is the keystone of the cellular response toward oxidative stress. Elevated GSH content correlates with increased resistance to chemotherapy and radiotherapy of head and neck (HN) tumors. Nuclear localization of glutamate-cysteine ligase is associated with proliferation in head and neck squamous cell carcinoma. The localization of GSH synthesis contributes to the protection against oxidative stress within hotspots of cell proliferation. The expression of glutamate-cysteine ligase (GCL) accounts for the increased GSH availability observed in head and neck squamous cell carcinoma (SCC). No role of the NRF2 and NF?kappaB signaling pathways in GCLM activation
physiological function
the enzyme is important in the biosynthesis of glutathione, the rate of GSH formation is limited by Gsh1 activity
physiological function
the enzyme is required for biosynthesis of glutathione. Glutathione (GSH) fulfills a variety of metabolic functions, participates in oxidative stress response, and defends against toxic actions of heavy metals and xenobiotics
physiological function
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expression of both glutamate-cysteine ligase catalytic and modifier subunit is mediated by the GCN2/ATF4 stress response pathway. Regulation of modifier subunit GCLM expression may be mediated by changes in the abundance of mRNA stabilizing or destabilizing proteins. Upregulation of GCLM levels in response to low cysteine levels may serve to protect the cell in the face of a future stress requiring GSH as an antioxidant or conjugating/detoxifying agent
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physiological function
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the bifunctional GSH synthetase catalyzes two steps in GSH synthesis, which are usually catalyzed through L-glutamate L-cysteine ligase (gamma-GCS) and L-glutathione synthetase (GS)
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physiological function
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the enzyme is important in the biosynthesis of glutathione, the rate of GSH formation is limited by Gsh1 activity
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physiological function
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the enzyme is required for biosynthesis of glutathione. Glutathione (GSH) fulfills a variety of metabolic functions, participates in oxidative stress response, and defends against toxic actions of heavy metals and xenobiotics
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additional information
GCL is a heterodimeric enzyme, consisting of a catalytic subunit, (GCLc) and a modulatory subunit (GCLm) that are encoded by two distinct genes. GCLc constitutes all the enzymatic activity, but catalytic efficiency is increased substantially by covalent interaction with GCLm
additional information
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GCL is a heterodimeric enzyme, consisting of a catalytic subunit, (GCLc) and a modulatory subunit (GCLm) that are encoded by two distinct genes. GCLc constitutes all the enzymatic activity, but catalytic efficiency is increased substantially by covalent interaction with GCLm
additional information
MALDI-TOF mass spectrometric analysis of tryptic peptides, mapping of the identify the cysteinyl residue target of the S-glutathionylation reaction, which occurs at the Cys residue at position 386. Three-dimensional model of rPhGshA II obtained by homology modelling, overview. The catalytic residue Cys 386 is located at the protein surface
additional information
positive interaction between two subunits of glutamate-cysteine ligase is detected using the yeast two-hybrid system. Enzyme protein structure prediction using the glutamate-cysteine ligase in complex with Mg2+ and L-glutamate, comparisons of tertiary structures, overview
additional information
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positive interaction between two subunits of glutamate-cysteine ligase is detected using the yeast two-hybrid system. Enzyme protein structure prediction using the glutamate-cysteine ligase in complex with Mg2+ and L-glutamate, comparisons of tertiary structures, overview
additional information
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MALDI-TOF mass spectrometric analysis of tryptic peptides, mapping of the identify the cysteinyl residue target of the S-glutathionylation reaction, which occurs at the Cys residue at position 386. Three-dimensional model of rPhGshA II obtained by homology modelling, overview. The catalytic residue Cys 386 is located at the protein surface
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