Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.3.2.3 (glutathione synthetase)
678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well known that intracellular antioxidant glutathione (GSH) plays major roles in the maintenance of redox status and defense of oxidative stress. Ras, a small GTP-binding protein, may send growth-stimulating message to the nucleus through downstream Rac oncoprotein and superoxide (O(2*-)). These findings led us to investigate the effects of GSH and melatonin, a free-radical scavenger, on Ras-Rac-O(2*-)-related growth signal transduction. Our results demonstrate that overexpression of the inducible Ha-ras oncogene by isopropyl-beta-D-thiogalactoside (IPTG) increases the levels of reactive oxygen species (ROS, including O(2*-) and hydrogen peroxide (H(2)O(2))) and GSH in an Ha-ras-transformed NIH/3T3 fibroblast cell line. On the contrary, melatonin significantly suppresses ras-triggered cell growth by inhibiting the increase of ROS and GSH. Moreover, severe apoptosis of this transformed cell line occurred when the cell redox balance between ROS and GSH was dramatically changed in the presence of IPTG and L-buthionine-[S,R]-sulfoximine (BSO, a specific inhibitor of GSH synthetase). That BSO-induced cell apoptosis needs Ras to increase the ROS level was demonstrated by the free-radical scavenger melatonin. It effectively blocked cell apoptosis, but cell growth was also slowed without affecting Ras expression. Based on our studies, two approaches can be applied to treating ras-related cancers. One is utilizing melatonin to suppress cancer cell proliferation, and the other is utilizing BSO to induce cancer-cell apoptosis. Cotreatment of ras-related cancer cells with melatonin and BSO stops cell growth as well as apoptosis. Whether these cancer cells will undergo further regression or become recurrent merits investigation.
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PMID:Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be prevented by melatonin. 1261 60

Conformational changes of three flexible loops (G, A, and S) in human glutathione synthetase (hGS) arise to accommodate the substrates inside the active site. The crystal structure of hGS, a member of the ATP-grasp superfamily, has been reported only for the product-enzyme complex. To study the function of the hGS loops, molecular dynamics simulations are performed on three different conformational models: unbound enzyme, reactant-enzyme, and product-enzyme complex of hGS. The conformational changes among the three models are analyzed and the roles of the loops during the catalytic process are described. The modeled structures of hGS show that the central portions of the G- and A-loop have a double role in the reactant complex conformation: they bind the substrates and simultaneously interact with each other through an extensive network of hydrogen bonds. The present study proposes that these favorable loop-ligand and loop-loop interactions are required for opening and closing of the active site of hGS. Additionally, this research identifies important amino acid residues and explains their function within the catalytic loops of hGS.
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PMID:Catalytic loop motion in human glutathione synthetase: A molecular modeling approach. 1718 41

Some members of lactic acid bacteria are known to synthesize glutathione (GSH) or to import it from growth medium, whereas others are not. Analysis of the genome sequences of several Leuconostoc spp. indicate the presence of the gene gshA that encodes gamma-glutamylcysteine synthetase, but not the gene gshB encoding glutathione synthetase. We report here that, in cells of Leuconostoc kimchii and Leuconostoc mesenteroides, gamma-glutamylcysteine (gamma-GC) is present in large amount, whereas GSH is not detectable. The level of gamma-GC was higher at the stationary phase than at the exponential phase. Expression of the gshA gene in Leuconostoc spp. analyzed by S1 mapping showed the increased mRNA level upon hydrogen peroxide treatment. From high-resolution S1 mapping, the transcriptional start site was mapped and the putative promoter elements were suggested. This work suggests that gamma-GC has a significant role in Leuconostoc spp. as the major low-molecular-weight thiol.
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PMID:Synthesis of gamma-glutamylcysteine as a major low-molecular-weight thiol in lactic acid bacteria Leuconostoc spp. 1832 77

Flavonoids are plant-derived polyphenolic compounds with neuroprotective properties. Recent work suggests that, in addition to acting as hydrogen donors, they activate protective signalling pathways. The anti-oxidant response element (ARE) promotes the expression of protective proteins including those required for glutathione synthesis (xCT cystine antiporter, gamma-glutamylcysteine synthetase and glutathione synthase). The use of a luciferase reporter (ARE-luc) assay showed that the dietary flavan-3-ol (-)epicatechin activates this pathway in primary cortical astrocytes but not neurones. We also examined the distribution of NF-E2-related factor-2 (Nrf2), a key transcription factor in ARE-mediated gene expression. We found, using immunocytochemistry, that Nrf2 accumulated in the nuclei of astrocytes following exposure to tert-butylhydroquinone (100 microM) and (-)epicatechin (100 nM). (-)Epicatechin signalling via Nrf2 was inhibited by wortmannin implicating a phosphatidylinositol 3-kinase-dependent pathway. Finally, (-)epicatechin increased glutathione levels in astrocytes consistent with an up-regulation of ARE-mediated gene expression. Together, this suggests that flavonoids may be cytoprotective by increasing anti-oxidant gene expression.
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PMID:Dietary flavonoid (-)epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes. 1862 17

The effect of stress hormones and abiotic stress treatments on reactive oxygen species and on antioxidants was compared in two maize (Zea mays L.) lines (Penjalinan and Z7) having different stress tolerance. Following treatment with abscisic acid, salicylic acid or hydrogen peroxide, the amount of hydrogen peroxide and lipid peroxides increased, while after osmotic stress or cultivation in continuous darkness, the levels were unchanged or decreased. The higher amount of lipid peroxides in Penjalinan indicated its greater sensitivity compared to Z7. The level of the examined antioxidants was increased by nearly all treatments. Glutathione and cysteine contents were higher after salicylic acid, hydrogen peroxide and polyethylene glycol treatments and lower after application of abscisic acid, NaCl and growth in darkness in Z7 than in Penjalinan. The activity of glutathione reductase, ascorbate peroxidase, catalase and glutathione S-transferase was higher after almost all treatments in Z7. The expression of the glutathione synthetase (EC 6.3.2.3) gene was not affected by the treatments, while the level of gamma-glutamylcysteine synthetase (EC 6.3.2.2) and glutathione reductase (EC 1.6.4.2) transcripts increased after most treatments. The two stress hormones and the stress treatments resulted in different changes in antioxidant levels in the two maize lines, which indicates the specific, stress tolerance-dependent response of plants to the various growth regulators and adverse environmental effects that were examined.
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PMID:Stress hormones and abiotic stresses have different effects on antioxidants in maize lines with different sensitivity. 1876 95

While the toxicity of hexavalent chromium is well established, trivalent chromium is an essential nutrient involved in insulin and glucose homeostasis. To study the antioxidant effects of Cr(III)His, cDNA arrays were used to investigate the modulation of gene expression by trivalent chromium histidinate (Cr(III)His) in HaCaT human keratinocytes submitted to hydrogen peroxide (H2O2). Array was composed by a set of 81 expressed sequences tags (ESTs) essentially represented by antioxidant and DNA repair genes. HaCaT were preincubated for 24 h with 50 microM Cr(III)His and were treated with 50 muM H2O2. Total RNAs were isolated immediately or 6 h after the stress. In Cr(III)His preincubated cells, transcripts related to antioxidant family were upregulated (glutathione synthetase, heme oxygenase 2, peroxiredoxin 4). In Cr(III)His preincubated cells and exposed to H2O2, increased expressions of polymerase delta 2 and antioxidant transcripts were observed. Biochemical methods performed in parallel to measure oxidative stress in cells showed that Cr(III)His supplementation before H2O2 stress protected HaCaT from thiol groups decrease and thiobarbituric acid reactive substances increase. In summary, these results give evidence of antioxidant gene expression and antioxidant protection in HaCaT preincubated with Cr(III)His and help to explain the lack of toxicity reported for Cr(III)His.
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PMID:Chromium III histidinate exposure modulates gene expression in HaCaT human keratinocytes exposed to oxidative stress. 1990 59

5-Oxoproline accumulates in glutathione synthetase deficiency, an autossomic recessive inherited disorder clinically characterized by hemolytic anemia, metabolic acidosis, and severe neurological symptoms whose mechanisms are poorly known. In the present study we investigated the effects of acute subcutaneous administration of 5-oxoproline to verify whether oxidative stress is elicited by this metabolite in vivo in cerebral cortex and cerebellum of 14-day-old rats. Our results showed that the acute administration of 5-oxoproline is able to promote both lipid and protein oxidation, to impair brain antioxidant defenses, to alter SH/SS ratio and to enhance hydrogen peroxide content, thus promoting oxidative stress in vivo, a mechanism that may be involved in the neuropathology of gluthatione synthetase deficiency.
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PMID:Acute administration of 5-oxoproline induces oxidative damage to lipids and proteins and impairs antioxidant defenses in cerebral cortex and cerebellum of young rats. 2043 31

Overexpression of thioredoxin (TRX) confers oxidative stress resistance and extends lifespan in mammals and insects. However, less is known about phenotypes associated with loss of TRX. We investigated loss-of-function phenotypes of Trx-2 in Drosophila, and found that the mutant flies are hyper-susceptible to paraquat, a free radical generator, but not to hydrogen peroxide. They contain a high amount of protein carbonyl, which dramatically increases with age. Trx-2 mutants express high levels of anti-oxidant genes, such as superoxide dismutase, catalase, and glutathione synthetase. This is the first demonstration of biochemical and physiological consequences caused by loss of Trx-2 in Drosophila.
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PMID:Loss of Trx-2 enhances oxidative stress-dependent phenotypes in Drosophila. 2060 5

Peach fruits were selected to study the protein pattern and antioxidant system as well as oxidative parameters such as superoxide radical and hydrogen peroxide accumulation, at two maturity stages, which were chosen for being suitable for the processing industry and fresh consumption. The proteins phosphoenolpyruvate carboxylase, sucrose synthase, and 1-aminocyclopropane-1-carboxylate oxidase, as well as the antioxidants glutathione synthetase and ascorbate peroxidase, appeared as new in the mature peach fruits. Activities of superoxide dismutase (SOD) and components of the ascorbate-glutathione cycle were also measured to explore their role in the two maturity stages studied. Changes in the SOD isoenzyme pattern and an increase in the activities of ascorbate peroxidase, monodehydroascorbate reductase, and glutathione reductase were observed in mature fruits, revealing an efficient system to cope with the oxidative process accompanying ripening.
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PMID:Antioxidant system and protein pattern in peach fruits at two maturation stages. 2087 12

The stable HepG2 transfectants anti-sensing expression of the glutathione synthetase (GS) gene exhibited delayed cell growth and increased reactive oxygen species (ROS) level. After the treatment with hydrogen peroxide, the intracellular ROS level was much higher in the stable transfectants than in the vector control cells. However, the GSH levels decreased more significantly in the stable transfectants than in the vector control cells, in the presence of hydrogen peroxide. Hydrogen peroxide-induced apoptosis of the stable transfectants was notably higher than that of the vector control cells. The GS anti-sense RNAs rendered the HepG2 cells more sensitive to growth arrest caused by glucose deprivation. They also sensitized the HepG2 cells to cadmium chloride (Cd) and nitric oxide (NO)-generating sodium nitroprusside (SNP). In brief, the results confirm that GS plays an important role in the defense of the human hepatoma cells against oxidative stress by reducing apoptosis and maintaining redox homeostasis.
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PMID:Disruption of redox homeostasis and induction of apoptosis by suppression of glutathione synthetase expression in a mammalian cell line. 2167 55


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