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)

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

This Mini-Review summarizes the historic developments and technological achievements in the biotechnological production of glutathione in the past 30 years. Glutathione is the most abundant non-protein thiol compound present in living organisms. It is used as a pharmaceutical compound and can be used in food additives and the cosmetic industries. Glutathione can be produced using enzymatic methods in the presence of ATP and its three precursor amino acids (L-glutamic acid, L-cysteine, glycine). Alternatively, glutathione can be produced by direct fermentative methods using sugar as a starting material. In the latter method, Saccharomyces cerevisiae and Candida utilis are currently used to produce glutathione on an industrial scale. At the molecular level, the genes gshA and gshB, which encode the enzymes gamma-glutamylcysteine synthetase and glutathione synthetase, respectively, have been cloned from Escherichia coli and over-expressed in E. coli, S. cerevisiae, and Lactococcus lactis. It is anticipated that, with the design and/or discovery of novel producers, the biotechnological production of glutathione will be further improved to expand the application range of this physiologically and medically important tripeptide.
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PMID:Glutathione: a review on biotechnological production. 1548 Jun 25

Glutathione and gamma-glutamylcysteine were produced in Lactococcus lactis using a controlled expression system and the genes gshA and gshB from Escherichia coli encoding the enzymes gamma-glutamylcysteine synthetase and glutathione synthetase. High levels of gamma-glutamylcysteine were found in strains growing on chemically defined medium and expressing either gshA alone or both gshA and gshB. As anticipated, glutathione was found in a strain expressing gshA and gshB. The level of glutathione production could be increased by addition of the precursor amino acid cysteine to the medium. The addition of cysteine led to an increased activity of glutathione synthetase, which is remarkable because the amino acid is not a substrate of this enzyme. The final intracellular glutathione concentration attained was 358 nmol mg(-1) protein, which is the highest concentration reported for a bacterium, demonstrating the suitability of engineered L. lactis for fine-chemical production and as a model for studies of the impact of glutathione on flavour formation and other properties of food.
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PMID:Using Lactococcus lactis for glutathione overproduction. 1549 Jan 55

Glutathione (GSH) is in a constant state of metabolic turnover. Because it is actively synthesized, it also must be degraded. In the first step of GSH synthesis, an amide linkage is formed between cysteine and glutamate catalyzed by gamma-glutamylcysteine synthetase. GSH synthetase catalyzes the reaction between amine residue of glycine and the cysteine carboxyl from gamma-glutamylcysteine dipeptide to form GSH. GSH is transported out of the cell and degraded by the membrane-bound enzyme gammaGT, which removes the gamma-glutamyl moiety, and by dipeptidases, which remove the glycine moiety. Glutathione is present in most of the plants and animals' tissues that constitute human diet. Thiol redox cycles play central roles in the antioxidant defense network. Lipoate and vitamins and other reducing factors affect the increase in glutathione concentrations in cells by the rise of the concentrations of reduced cysteine. The level of GSH in humans may be increased by taking different glutathione monoester (drug) or factors reducing cystyne to cysteine and increasing availability of this amino acid to GSH synthesis. GSH plays a critical role in cellular mechanisms that lead to cell death. The cancer cells resistant to apoptosis have higher intracellular GSH levels. The fact that numerous diseases are induced by RFT (that cause glutathione depletion) it seems that an in-depth study of the dietetic and pharmacological manners of manipulation of the GSH amount and availability may become in future a tool of great importance in the prevention of many illnesses.
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PMID:[Glutathione: its biosynthesis, induction agents and concentrations in selected diseases]. 1588 20

GSH synthesis occurs through a two-step enzymatic reaction driven by GCL (glutamate-cysteine ligase; made up of catalytic and modifying subunits) and GSS (glutathione synthetase). In humans, oxidative stress regulates GCL expression in an antioxidant response element-dependent manner via Nrf2 [NFE (nuclear factor erythroid)-related factor 2]. In the rat, GSS and GCL are regulated co-ordinately by oxidative stress, and induction of GSS further increases GSH synthetic capacity. Transcriptional regulation of the human GSS has not been examined. To address this, we have cloned and characterized a 2.2 kb 5'-flanking region of the human GSS. The transcriptional start site is located 80 nt upstream of the translation start site. The human GSS promoter efficiently drove luciferase expression in Chang cells. Overexpression of either Nrf1 or Nrf2 induced the GSS promoter activity by 130 and 168% respectively. Two regions homologous to the NFE2 motif are demonstrated to be important for basal expression of human GSS, as mutation of these sites reduced the promoter activity by 66%. Nrf1, Nrf2 and c-Jun binding to these NFE2 sites under basal conditions was demonstrated using chromatin immunoprecipitation assays. In summary, two NFE2 sites in the human GSS promoter play important roles in the basal expression of GSS and, similar to the GCL subunits, the human GSS gene expression is also regulated by Nrf2.
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PMID:Cloning and characterization of the human glutathione synthetase 5'-flanking region. 1589 65


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