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biotechnology
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a protein transduction approach whereby recombinant GCL protein can be rapidly and directly transferred into cells when coupled to the HIV TAT protein transduction domain. The TAT-GCL fusion proteins are capable of heterodimerization and formation of functional GCL holoenzyme in vitro. Exposure of Hepa-1c1c7 cells to the TAT-GCL fusion proteins results in the time- and dose-dependent transduction of both GCL subunits and increased cellular GCL activity and glutathione levels. A heterodimerization-competent, enzymatically deficient GCLC-TAT mutant was also generated in an attempt to create a dominant-negative suppressor of GCL
drug development
the enzyme is a target for development of specific enzyme inhibitors in the treatment of ancylostomiasis
agriculture
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comparison of three transgenic poplar lines over-expressing the Escherichia coli gamma-glutamylcysteine synthetase. The three lines differ in their expression levels of the transgene and in the accumulation of gamma-glutamylcysteine and glutathione in leaves, roots and phloem exudates. The lowest transgene expression level is observed in line Lggs6 which shows an increased growth, an enhanced rate of photosynthesis and a decreased excitation pressure. Line Lggs12 shows the highest transgene expression level, highest gamma-glutamylcysteine accumulation in leaves and highest glutathione enrichment in phloem exudates and roots. This line also exhibits a reduced growth, and after a prolonged growth of 4.5 months, symptoms of leaf injury
agriculture
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expression of GCS via agroinfection in the heavy metal intolerant grass Agrostis palustris. GCS and phytochelatin synthase are up-regulated in the transgenic lines. All the transgenic lines accumulate more Cd2+ and phytochelatins than the wild-type line, and three of five lines grow more effectively than the wild-type after either five or 21 days of Cd2+ stress. Variation among the transgenics is observed for the distribution of Cd2+ in the root, shoot and leaf. The malondialdehyde content of all the transgenic lines is lower than that of the wild type under Cd2+ treatment, while the activity of both superoxide dismutase and peroxidase present in the transgenic lines increases markedly 24 h after Cd2+ stress, and then rapidly declines
agriculture
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transformation of GCS gene via agroinfection into the heavy metal intolerant grass Agrostis palustris results in upregulation of GCS and phytochelatin synthase in the transgenic lines. Transgenic lines accumulate more Cd2+ and phytochelatins than the wild-type line, and three of five lines grow more effectively than the wild-type after either five or 21 d of Cd2+ stress. Variation among the transgenics is observed for the distribution of Cd2+ in the root, shoot and leaf. The malondialdehyde content of all the transgenic lines is lower than that of the wild type under Cd2+ treatment, while the activity of both superoxide dismutase and peroxidase present in the transgenic lines increases markedly 24 h after Cd2+ stress, and then rapidly declines
medicine
enzyme inhibitor L-buthionine-S-sulfoximine is used to modulate GSH levels in cancer patients, overview
medicine
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the enzyme is a target for development of potential therapeutic agents
medicine
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the enzyme may be a key factor in the chemopreventive potential of coffee components kahweol and cafestol
medicine
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gamma-GCS gene is the downstream target of c-Myc oncoprotein, driving the response to ROS-inducing drugs. gamma-GCS impairment might specifically sensitize high c-Myc tumor cells to chemotherapy
medicine
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activation of glycogen synthase kinase 3beta is a key mediator of the initial phase of acetaminophen-induced liver injury through modulating GCL and Mcl-1 degradation, as well as JNK activation in liver. The silencing of glycogen synthase kinase 3beta decreases the loss of hepatic GCL, and promotes greater GSH recovery in liver following acetaminophen treatment
medicine
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mice lacking the glutamate-cysteine ligase modifier subunit are susceptible to myocardial ischaemia-reperfusion injury partly through an increased vulnerability of mitochondria to oxidative damage owing to mitochondrial glutathione reduction
medicine
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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
medicine
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the presence of at least one T allele in the -129 C/T polymorphism of the GCL catalytic subunit gene is independently associated with non-alcoholic steatohepatitis
medicine
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study on recombinant Leishmania donovani gammaglutamyl cysteine synthetase protein alone or incorporated into a non-ionic surfactant vesicle delivery system to protect against Leishmania donovani infection in a BALB/c mouse model. Immunization with gammaglutamyl cysteine synthetase alone or gammaglutamyl cysteine synthetase-NIV induces specific IgG1 and IgG2a antibodies compared to controls, with gammaglutamyl cysteine synthetase-NIV inducing significantly higher titers of both antibody classes. Both formulations induce similar increases in splenocyte IFN-gamma production following ex vivo antigen stimulation with gammaglutamyl cysteine synthetase compared with cells from control mice. Similar levels of protection against infection are induced by gammaglutamyl cysteine synthetase alone and gammaglutamyl cysteine synthetase-NIV, based on their ability to suppress liver parasite burdens compared to control values
medicine
suitability of treatment of humans with exogenous enzyme gamma-GC to raise GSH levels by circumventing the age-related dysregulation of the rate-limiting step of GSH, providing promise for future research for the treatment of chronic oxidative stress-related diseases
medicine
the enzyme is a target for development of a vaccination against ancylostomiasis
medicine
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the enzyme is a target for development of potential therapeutic agents
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pharmacology
the enzyme is a potential drug target
pharmacology
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co-treatment by indomethacin and doxorubicin increases the cytotoxicitiy of doxorubicin by decreasing the intracellular contents of glutathione and its conjugates with decreasing expression of gamma-glutamylcysteine synthetase. Indomethacin inhibits the gamma-glutamylcysteine synthetase promoter activity.
pharmacology
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rat model of glutathione depletion using an adenovirus vector with short hairpin RNA against gamma-glutamylcysteine synthetase heavy chain subunit. In the acute 6 or 24 h or subacute 7 days toxicity tests, rats were administered the drugs once or once a day for a week, respectively. Plasma biochemical markers for hepatotoxicity were measured. The 6 and 24 h toxicity test of diclofenac, and the 24 h and 7 days toxicity tests of flutamide show significant serum alanine aminotransferase elevations. The 24 h toxicity test of flutamide shows a slight bilirubin elevation, and histological hepatotoxicity. The 7 days toxicity test of flutamide also demonstrates histological hepatotoxicity
pharmacology
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
synthesis
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resting cells of Escherichia coli expressing gamma-glutamylcysteine synthetase, with ATP regeneration through glycolysis, synthesize 12.1 mM theanine in 18 h from 429 mM ethylamine
synthesis
at elevated concentrations of the precursor amino acids and ATP, Escherichia coli JM109 pTrc99A-gshF produces 36 mM GSH with a molar yield of 0.9 mol/mol based on added cysteine and of 0.45 mol/mol based on added ATP. When ATP is replaced with glucose, the strain produces 7 mM in 3 h. In the presence of glucose and the pmr1 mutant of Saccharomyces cerevisiae BY4742 for ATP generation, Escherichia coli JM109 pTrc99A-gshF produces 33.9 mM GSH in 12 h with a yield of 0.85 mol/mol based on added l-cysteine
synthesis
Rhodosporidium diobovatum with its GSH1 and GSH2 genes can be useful for industrial GSH production
synthesis
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at elevated concentrations of the precursor amino acids and ATP, Escherichia coli JM109 pTrc99A-gshF produces 36 mM GSH with a molar yield of 0.9 mol/mol based on added cysteine and of 0.45 mol/mol based on added ATP. When ATP is replaced with glucose, the strain produces 7 mM in 3 h. In the presence of glucose and the pmr1 mutant of Saccharomyces cerevisiae BY4742 for ATP generation, Escherichia coli JM109 pTrc99A-gshF produces 33.9 mM GSH in 12 h with a yield of 0.85 mol/mol based on added l-cysteine
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synthesis
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Rhodosporidium diobovatum with its GSH1 and GSH2 genes can be useful for industrial GSH production
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