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)

The cellular defense system (including glutathione, glutathione-related enzymes, antioxidant and redox enzymes) plays a crucial role in cell survival and growth in aerobic organisms. To understand its physiological role in tumor cells, the glutathione content and related enzyme activities in the human normal hepatic cell line, Chang and human hepatoma cell line, HepG2, were systematically measured and compared. Superoxide dismutase, catalase, and glutathione peroxidase activities are 2.8-, 4.3-, and 2.9-fold higher in HepG2 cells than in Chang cells. Total glutathione content is also about 1.4-fold higher in HepG2, which is supported by significant increases in gamma-glutamylcysteine synthetase and glutathione synthetase activities. Two other glutathione-related enzymes, glutathione reductase and gamma-glutamyltranspeptidase, are upregulated in HepG2 cells. However, thioredoxin reductase and glutathione S-transferase activities are significantly lower in HepG2 cells. These results propose that defense-related enzymes are largely modulated in tumor cells, which might be linked to their growth and maintenance.
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PMID:Activities of antioxidant and redox enzymes in human normal hepatic and hepatoma cell lines. 1244 6

Although Cd(2+) is a more effective inducer of phytochelatin (PC) synthesis than Zn(2+) in higher plants, we have observed greater induction of PC synthesis by Zn(2+) than Cd(2+) in the marine green alga, Dunaliella tertiolecta. To elucidate this unique regulation of PC synthesis by Zn(2+), we investigated the effects of Zn(2+) and Cd(2+) on the activities of both phytochelatin synthase (PC synthase) and enzymes in the GSH biosynthetic pathway. PC synthase was more strongly activated by Cd(2+) than by Zn(2+), but the difference was not very big. On the other hand, gamma-glutamylcysteine synthetase (gamma-ECS) and glutathione synthetase (GS) were activated by both heavy metals, but their activities were higher in Zn-treated cells than in Cd-treated cells. Dose-dependent stimulation of intracellular reactive oxygen species (ROS) production was observed with Zn(2+), but not Cd(2+) treatment. These results suggest that Zn(2+) strongly promotes the synthesis of GSH through indirect activation of gamma-ECS and GS by stimulating ROS generation. This acceleration of the flux rate for GSH synthesis might mainly contribute to high level PC synthesis.
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PMID:Regulation of phytochelatin synthesis by zinc and cadmium in marine green alga, Dunaliella tertiolecta. 1262 Mar 58

Transgenic Indian mustard [Brassica juncea (L.) Czern.] plants overproducing the enzymes gamma-glutamylcysteine synthetase (ECS) or glutathione synthetase (GS) were shown previously to have increased levels of the metal-binding thiol peptides phytochelatins and glutathione, and enhanced Cd tolerance and accumulation. Furthermore, transgenic Indian mustard plants overexpressing adenosine triphosphate sulfurylase (APS) were shown to have higher levels of glutathione and total thiols. These results were obtained with a solution culture. To better examine the phytoremediation potential of these transgenics, a greenhouse experiment was performed in which the transgenics were grown on metal-contaminated soil collected from a USEPA Superfund site near Leadville, Colorado. A grass mixture used for revegetation of the site was included for comparison. The ECS and GS transgenics accumulated significantly (P < 0.05) more metal in their shoot than wild-type (WT) Indian mustard, while the APS plants did not. Of the six metals tested, the ECS and GS transgenics accumulated 1.5-fold more Cd, and 1.5- to 2-fold more Zn, compared with wild-type Indian mustard. Furthermore, the ECS transgenics accumulated 2.4- to 3-fold more Cr, Cu, and Pb, relative to WT. The grass mixture accumulated significantly less metal than Indian mustard: approximately 2-fold less Cd, Cu, Mn, and Zn, and 5.7-fold less Pb than WT Indian mustard. All transgenics removed significantly more metal from the soil compared with WT Indian mustard or an unplanted control. While WT did not remove more metal than the unplanted control for any of the metals tested, all three types of transgenics significantly reduced the soil metal concentration, and removed between 6% (Zn) and 25% (Cd) of the soil metal. This study is the first to demonstrate enhanced phytoextraction potential of transgenic plants using polluted environmental soil. The results confirm the importance of metal-binding peptides for plant metal accumulation and show that results from hydroponic systems have value as an indicator for phytoremediation potential.
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PMID:Analysis of transgenic Indian mustard plants for phytoremediation of metal-contaminated mine tailings. 1270 65

The fission yeast cells that contained the cloned glutathione synthetase (GS) gene showed 1.4-fold higher glutathione (GSH) content and 1.9-fold higher GS activity than the cells without the cloned GS gene. Interestingly, gamma-glutamylcysteine synthetase activity increased 2.1-fold in the S. pombe cells that contained the cloned GS gene. The S. pombe cells that harbored the multicopy-number plasmid pRGS49 (containing the cloned GS gene) showed a higher level of survival on solid media with cadmium chloride (1 mM) or mercuric chloride (10 microM) than the cells that harbored the YEp357R vector. The 506 bp upstream sequence from the translational initiation point and N-terminal 8 amino acid-coding region were fused into the promoterless beta-galactosidase gene of the shuttle vector YEp367R to generate the fusion plasmid pUGS39. Synthesis of beta-galactosidase from the fusion plasmid pUGS39 was significantly enhanced by cadmium chloride and NO-generating S-nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside (SN). It was also induced by L-buthionine-(S,R)-sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase (GCS). We also found that the expression of the S. pombe GS gene is regulated by the Atf1-Spc1-Wis1 signal pathway.
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PMID:Regulation of the gene encoding glutathione synthetase from the fission yeast. 1278 90

In the protozoan parasite Leishmania, drug resistance can be a complex phenomenon. Several metabolic pathways and membrane transporters are implicated in the resistance phenotype. To monitor the expression of these genes, we generated custom DNA microarrays with PCR fragments corresponding to 44 genes involved with drug resistance. Transcript profiling of arsenite and antimony resistant mutants with these arrays pinpointed a number of genes overexpressed in mutants, including the ABC transporter PGPA, the glutathione biosynthesis genes gamma-glutamylcysteine synthetase (GSH1) and the glutathione synthetase (GSH2). Competitive hybridisations with total RNA derived from sensitive and methotrexate resistant cells revealed the overexpression of genes coding for dihydrofolate reductase (DHFR-TS), pteridine reductase (PTR1) and S-adenosylmethionine synthase (MAT2) and a down regulation of one gene of the folate transporter (FT) family. By labelling the DNA of sensitive and resistant parasites we could also detect several gene amplification events using DNA microarrays including the amplification of the S-adenosyl homocysteine hydrolase gene (SAHH). Alteration in gene expression detected by microarrays was validated by northern blot analysis, while Southern blots indicated that most genes overexpressed were also amplified, although other mechanisms were also present. The microarrays were useful in the study of resistant parasites to pinpoint several genes linked to drug resistance.
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PMID:Modulation of gene expression in Leishmania drug resistant mutants as determined by targeted DNA microarrays. 1453 Apr 37

The thiol tripeptides, glutathione (GSH) and homoglutathione (hGSH), perform multiple roles in legumes, including protection against toxicity of free radicals and heavy metals. The three genes involved in the synthesis of GSH and hGSH in the model legume, Lotus japonicus, have been fully characterized and appear to be present as single copies in the genome. The gamma-glutamylcysteine synthetase (gamma(ecs)) gene was mapped on the long arm of chromosome 4 (70.0 centimorgans [cM]) and consists of 15 exons, whereas the glutathione synthetase (gshs) and homoglutathione synthetase (hgshs) genes were mapped on the long arm of chromosome 1 (81.3 cM) and found to be arranged in tandem with a separation of approximately 8 kb. Both genes consist of 12 exons of exactly the same size (except exon 1, which is similar). Two types of transcripts were detected for the gshs gene, which putatively encode proteins localized in the plastids and cytosol. Promoter regions contain cis-acting regulatory elements that may be involved in the plant's response to light, hormones, and stress. Determination of transcript levels, enzyme activities, and thiol contents in nodules, roots, and leaves revealed that gamma(ecs) and hgshs are expressed in all three plant organs, whereas gshs is significantly functional only in nodules. This strongly suggests an important role of GSH in the rhizobia-legume symbiosis.
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PMID:Molecular analysis of the pathway for the synthesis of thiol tripeptides in the model legume Lotus japonicus. 1460 72

Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.
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PMID:Glutathione metabolism and its implications for health. 1498 35

To investigate the intercellular control of glutathione synthesis and its influence on leaf redox state in response to short-term chilling, genes encoding gamma-glutamylcysteine synthetase (gamma-ECS) and glutathione synthetase (GSH-S) were cloned from maize (Zea mays) and specific antibodies produced. These tools were used to provide the first information on the intercellular distribution of gamma-ECS and GSH-S transcript and protein in maize leaves, in both optimal conditions and chilling stress. A 2-d exposure to low growth temperatures (chill) had no effect on leaf phenotype, whereas return to optimal temperatures (recovery) caused extensive leaf bleaching. The chill did not affect total leaf GSH-S transcripts but strongly induced gamma-ECS mRNA, an effect reversed during recovery. The chilling-induced increase in gamma-ECS transcripts was not accompanied by enhanced total leaf gamma-ECS protein or extractable activity. In situ hybridization and immunolocalization of leaf sections showed that gamma-ECS and GSH-S transcripts and proteins were found in both the bundle sheath (BS) and the mesophyll cells under optimal conditions. Chilling increased gamma-ECS transcript and protein in the BS but not in the mesophyll cells. Increased BS gamma-ECS was correlated with a 2-fold increase in both leaf Cys and gamma-glutamylcysteine, but leaf total glutathione significantly increased only in the recovery period, when the reduced glutathione to glutathione disulfide ratio decreased 3-fold. Thus, while there was a specific increase in the potential contribution of the BS cells to glutathione synthesis during chilling, it did not result in enhanced leaf glutathione accumulation at low temperatures. Return to optimal temperatures allowed glutathione to increase, particularly glutathione disulfide, and this was associated with leaf chlorosis.
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PMID:Intercellular distribution of glutathione synthesis in maize leaves and its response to short-term chilling. 1504 2

The glutathione redox couple is an information-rich redox buffer that interacts with numerous cellular components. To explore the role of glutathione in redox signalling, leaf contents were increased either chemically, by feeding reduced glutathione (GSH), or genetically, by over-expressing the first enzyme of the GSH biosynthetic pathway, gamma-glutamylcysteine synthetase (gamma-ECS). Leaf discs were also fed glutathione disulphide (GSSG), leading to increases in both GSH and GSSG. The effects of increases in GSH were compared with non-specific changes in leaf thiol status induced by feeding dithiothreitol (DTT) or the monothiol beta-mercaptoethanol (beta-ME). Photosynthesis measurements showed that none of the feeding treatments greatly disrupted leaf physiology. Transgenic plants expressing aequorin were used to analyse calcium signatures during the feeding treatments. Calcium release occurred soon after the onset of GSH or GSSG feeding, but was unaffected by DTT or beta-ME. Pathogenesis-related protein 1 (PR-1) was induced both in the gamma-ECS overexpressors and by feeding GSH, but not GSSG. Feeding DTT also induced PR-1. Key transcripts encoding antioxidative enzymes were much less affected, although glutathione synthetase was suppressed by feeding thiols or GSSG. It is concluded that modulation of glutathione contents transmits information through diverse signalling mechanisms, including (i) the establishment of an appropriate redox potential for thiol/disulphide exchange and (ii) the release of calcium to the cytosol.
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PMID:Regulation of calcium signalling and gene expression by glutathione. 1528 41

Skeletal muscle differentation is a complex process regulated at multiple levels. This study addressed the effect of glutathione (GSH) depletion on the transition of murine skeletal muscle C2C12 myoblasts into myocytes induced by growth factor inactivation. Cellular GSH levels increased within 24 hours on myogenic stimulation of myoblasts due to enhanced GSH synthetic rate accounted for by stimulated glutamate-L-cysteine ligase (also known as gamma-glutamylcysteine synthetase) activity. In contrast, the synthesis rate of GSH using gamma-glutamylcysteine and glutamate as precursors, which reflects the activity of the GSH synthetase, did not change during differentiation. The stimulation of GSH stores preceded the myogenic differentiation of C2C12 myoblasts monitored by expression of muscle-specific genes, creatine kinase (CK), myosin heavy chain (MyHC), and MyoD. The pattern of DNA binding activity of NF-kappaB and AP-1 in differentiating cells was similar both displaying an activation peak at 24 hours after myogenic stimulation. Depletion of cellular GSH levels 24 hours after stimulation of differentiation abrogated myogenesis as reflected by lower CK activity, MyHC levels, MyoD expression, and myotubes formation, effects that were reversible on GSH replenishment by GSH ethyl ester (GHSEE). Moreover, GSH depletion led to sustained activation of NF-kappaB, while GSHEE prevented it. Furthermore, inhibition of NF-kappaB activation restored myogenesis despite GSH depletion. Thus, GSH contributes to the formation of myotubes from satellite myoblasts by ensuring inactivation of NF-kappaB, and hence maintaining optimal GSH levels may be beneficial in restoring muscle mass in chronic inflammatory disorders.
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PMID:Glutathione depletion impairs myogenic differentiation of murine skeletal muscle C2C12 cells through sustained NF-kappaB activation. 1533 97


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