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)

Increased oxidative stress, which can arise from dietary, environmental and/or genetic sources, contributes to the decline in cognitive performance during normal aging and in neurodegenerative conditions such as Alzheimer's disease. Supplementation with fruits and vegetables that are high in antioxidant potential can compensate for dietary and/or genetic deficiencies that promote increased oxidative stress. We have recently demonstrated that apple juice concentrate (AJC) prevents the increase in oxidative damage to brain tissue and decline in cognitive performance observed when transgenic mice lacking apolipoprotein E (ApoE-/-) are maintained on a vitamin-deficient diet and challenged with excess iron (included in the diet as a pro-oxidant). However, the mechanism by which AJC provided neuroprotection was not conclusively determined. Herein, we demonstrate that supplementation with AJC also prevents the compensatory increases in glutathione synthase transcription and activity that otherwise accompany maintenance of ApoE-/- mice on this vitamin-free diet in the presence of iron. Inclusion of the equivalent composition and concentration of sugars of AJC did not prevent these increases. These findings provide further evidence that the antioxidant potential of AJC can compensate for dietary and genetic deficiencies that otherwise promote neurodegeneration.
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PMID:Dietary supplementation with apple juice concentrate alleviates the compensatory increase in glutathione synthase transcription and activity that accompanies dietary- and genetically-induced oxidative stress. 1554 22

The mechanism underlying Alzheimer's disease (AD), an age-related neurodegenerative disease, is still an area of significant controversy. Oxidative damage of macromolecules has been suggested to play an important role in the development of AD; however, the underlying mechanism is still unclear. In this study, we showed that the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, was decreased in red blood cells from male AD patients compared with age- and gender-matched controls. However, there was no difference in blood GSH concentration between the female patients and female controls. The decrease in GSH content in red blood cells from male AD patients was associated with reduced activities of glutamate cysteine ligase and glutathione synthase, the two enzymes involved in de novo GSH synthesis, with no change in the amount of oxidized glutathione or the activity of glutathione reductase, suggesting that a decreased de novo GSH synthetic capacity is responsible for the decline in GSH content in AD. These results showed for the first time that GSH metabolism was regulated differently in male and female AD patients.
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PMID:Gender differences in glutathione metabolism in Alzheimer's disease. 1569 22

Legumes form a symbiotic interaction with bacteria of the Rhizobiaceae family to produce nitrogen-fixing root nodules under nitrogen-limiting conditions. This process involves the recognition of the bacterial Nod factors by the plant which mediates the entry of the bacteria into the root and nodule organogenesis. We have examined the importance of the low molecular weight thiols, glutathione (GSH) and homoglutathione (hGSH), during the nodulation process in the model legume Medicago truncatula. Using both buthionine sulfoximine, a specific inhibitor of GSH and hGSH synthesis, and transgenic roots expressing GSH synthetase and hGSH synthetase in an antisense orientation, we showed that deficiency in GSH and hGSH synthesis inhibited the formation of the root nodules. This inhibition was not correlated to a modification in the number of infection events or to a change in the expression of the Rhizobium sp.-induced peroxidase rip1, indicating that the low level of GSH or hGSH did not alter the first steps of the infection process. In contrast, a strong diminution in the number of nascent nodules and in the expression of the early nodulin genes, Mtenod12 and Mtenod40, were observed in GSH and hGSH-depleted plants. In conclusion, GSH and hGSH appear to be essential for proper development of the root nodules during the symbiotic interaction.
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PMID:Glutathione and homoglutathione play a critical role in the nodulation process of Medicago truncatula. 1578 39

Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant mechanisms, including elements of the glutathione (GSH) pathway, undergo at least a transient compensatory increase that is apparently insufficient due to continued oxidative damage during disease progression. Mice deficient in apolipoprotein E, which provide a model for some aspects of AD, undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet, despite a compensatory increase in glutathione synthase transcription and activity as well as increased levels of GSH. Dietary supplementation with N-acetyl cysteine (1 g/kg diet), a cell-permeant antioxidant and GSH precursor, alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to those of normal mice maintained in the presence of folate. These data support the administration of antioxidant precursors to buffer oxidative damage in neurodegenerative disorders.
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PMID:N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency. 1585 51

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

Strain QM B1551 of Bacillus megaterium contains seven compatible plasmids: two small rolling circle plasmids and five theta-replicating plasmids with cross-hybridizing replicons. To expand our understanding of these plasmids, the replicon region (6.7 kb) from pBM300 was cloned, sequenced, and functionally characterized. Sequence analysis showed that the replication protein (RepM300) was highly homologous to two other plasmid Rep proteins of the same strain but to no other known proteins. Furthermore, the location of the replication origin was within the RepM300 coding region, and the origin contained three 12-base direct repeats. Deletion analysis of the replicon confirmed the role of the Rep protein and showed that open reading frame 2 (ORF2) was required for stability. However, the protein encoded by ORF2 is entirely different from the replicon stability proteins encoded by the other two replicons. The entire plasmid was isolated from the plasmid array by integrating a spectinomycin resistance gene and transforming a plasmidless strain, PV361. Complete sequencing showed that pBM300 was 26,300 bp long, had a G+C content of 35.2%, and contained 20 ORFs, two of which encoded proteins that had no similarity to other proteins in the database. The proteins encoded by the plasmid ORFs had similarity to proteins for mobilization and transfer, an integrase, a rifampin resistance protein, a cell wall hydrolase, glutathione synthase, and a biotin carboxylase. The similarities were to several gram-positive genera and a few gram-negative genera and archaea. oriT and ssoT-like regions were detected near two mob genes. These results suggest that pBM300 is a mobilizable hybrid plasmid that confers increased metabolic and germination ability on its host. Its replicon also helps define a new plasmid family.
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PMID:Molecular characterization of plasmid pBM300 from Bacillus megaterium QM B1551. 1593 3

GSH synthesis occurs via two enzymatic steps catalysed by GCL [glutamate-cysteine ligase, made up of GCLC (GCL catalytic subunit), and GCLM (GCL modifier subunit)] and GSS (GSH synthetase). Co-ordinated up-regulation of GCL and GSS further enhances GSH synthetic capacity. The present study examined whether TNFalpha (tumour necrosis factor alpha) influences the expression of rat GSH synthetic enzymes. To facilitate transcriptional studies of the rat GCLM, we cloned its 1.8 kb 5'-flanking region. TNFalpha induces the expression and recombinant promoter activities of GCLC, GCLM and GSS in H4IIE cells. TNFalpha induces NF-kappaB (nuclear factor kappaB) and AP-1 (activator protein 1) nuclear-binding activities. Blocking AP-1 with dominant negative c-Jun or NF-kappaB with IkappaBSR (IkappaB super-repressor, where IkappaB stands for inhibitory kappaB) lowered basal expression and inhibited the TNFalpha-mediated increase in mRNA levels of all three genes. While all three genes have multiple AP-1-binding sites, only GCLC has a NF-kappaB-binding site. Overexpression with p50 or p65 increased c-Jun mRNA levels, c-Jun-dependent promoter activity and the promoter activity of GCLM and GSS. Blocking NF-kappaB also lowered basal c-Jun expression and blunted the TNFalpha-mediated increase in c-Jun mRNA levels. TNFalpha treatment resulted in increased c-Jun and Nrf2 (nuclear factor erythroid 2-related factor 2) nuclear binding to the antioxidant response element of the rat GCLM and if this was prevented, TNFalpha no longer induced the GCLM promoter activity. In conclusion, both c-Jun and NF-kappaB are required for basal and TNFalpha-mediated induction of GSH synthetic enzymes in H4IIE cells. While NF-kappaB may exert a direct effect on the GCLC promoter, it induces the GCLM and GSS promoters indirectly via c-Jun.
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PMID:Tumour necrosis factor alpha induces co-ordinated activation of rat GSH synthetic enzymes via nuclear factor kappaB and activator protein-1. 1601 81

The SH compound glutathione (GSH) is involved in several fundamental functions in the cell, including protection against reactive oxygen species (ROS). Here, we studied the effect on oxidative DNA damage in cultured skin fibroblasts from patients with hereditary GSH synthetase deficiency. Our hypothesis was that GSH-deficient cells are more prone to DNA damage than control cells. Single cell gel electrophoresis (the comet assay) in combination with the formamidopyrimidine DNA glycosylase enzyme, which recognizes oxidative base modifications, was used on cultured fibroblasts from 11 patients with GSH synthetase deficiency and five control subjects. Contrary to this hypothesis, we found no significant difference in background levels of DNA damage between cells from patients and control subjects. To study the induction of oxidative DNA damage without simultaneous DNA repair, the cells were gamma-irradiated on ice and DNA single-strand breaks measured. The patient and control cells were equally sensitive to induction of single strand breaks by gamma-irradiation. Therefore, factors other than GSH protect DNA from oxidative damage. However, cells with a high background level of oxidative DNA damage were found to be more sensitive to ionizing radiation. This suggests that differences in background levels of oxidative DNA damage may depend on the cells' intrinsic protection against induction of oxidative damage.
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PMID:Oxidative DNA damage in cultured fibroblasts from patients with hereditary glutathione synthetase deficiency. 1603 37

AtATM3, an ATP-binding cassette transporter of Arabidopsis (Arabidopsis thaliana), is a mitochondrial protein involved in the biogenesis of iron-sulfur clusters and iron homeostasis in plants. Our gene expression analysis showed that AtATM3 is up-regulated in roots of plants treated with cadmium [Cd(II)] or lead (II); hence, we investigated whether this gene is involved in heavy metal tolerance. We found that AtATM3-overexpressing plants were enhanced in resistance to Cd, whereas atatm3 mutant plants were more sensitive to Cd than their wild-type controls. Moreover, atatm3 mutant plants expressing 35S promoter-driven AtATM3 were more resistant to Cd than wild-type plants. Since previous reports often showed that the cytosolic glutathione level is positively correlated with heavy metal resistance, we measured nonprotein thiols (NPSH) in these mutant plants. Surprisingly, we found that atatm3 contained more NPSH than the wild type under normal conditions. AtATM3-overexpressing plants did not differ under normal conditions, but contained less NPSH than wild-type plants when exposed to Cd(II). These results suggest a role for AtATM3 in regulating cellular NPSH level, a hypothesis that was further supported by our gene expression study. Genetic or pharmacological inhibition of glutathione biosynthesis led to the elevated expression of AtATM3, whereas expression of the glutathione synthase gene GSH1 was increased under Cd(II) stress and in the atatm3 mutant. Because the closest homolog of AtATM3 in fission yeast (Schizosaccharomyces pombe), HMT1, is a vacuolar membrane-localized phytochelatin-Cd transporter, it is tempting to speculate that glutathione-Cd(II) complexes formed in the mitochondria are exported by AtATM3. In conclusion, our data show that AtATM3 contributes to Cd resistance and suggest that it may mediate transport of glutamine synthetase-conjugated Cd(II) across the mitochondrial membrane.
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PMID:AtATM3 is involved in heavy metal resistance in Arabidopsis. 1646 80

The levels of cysteine (Cys), gamma-glutamylcysteine (gammaEC), and glutathione (GSH) were measured in the endosperms, scutella, roots, and shoots of maize (Zea mays L.) seedlings. GSH was the major thiol in roots, shoots, and scutella, Cys predominated in endosperms. The endosperm, scutellum, and functional phloem translocation were required for maintenance of GSH pools in roots and shoots of 6-day-old seedlings. Exposure of roots to 3 micromolar Cd, besides causing a decline in GSH, caused an accumulation of gammaEC, as if the activity of GSH synthetase was reduced in vivo. [(35)S]Cys injected into endosperms of seedlings was partly metabolized to [(35)S]sulfate. The scutella absorbed both [(35)S]sulfate and [(35)S]Cys and transformed 68 to 87% of the radioactivity into [(35)S]GSH. [(35)S]GSH was translocated to roots and shoots in proportion to the tissue fresh weight. Taken together, the data supported the hypothesis that Cys from the endosperm is absorbed by the scutellum and used to synthesize GSH for transfer through the phloem to the root and shoot. The estimated flux of GSH to the roots was 35 to 60 nanomoles per gram per hour, which totally accounted for the small gain in GSH in roots between days 6 and 7. For Cd-treated roots the GSH influx was similar, yet the GSH pool did not recover to control levels within 24 hours. The estimated flux of GSH to the entire shoot was like that to the roots; however, it was low (11-13 nanomoles per gram per hour) to the first leaf and high (76-135 nanomoles per gram per hour) to the second and younger leaves.
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PMID:Cysteine, gamma-Glutamylcysteine, and Glutathione Levels in Maize Seedlings : Distribution and Translocation in Normal and Cadmium-Exposed Plants. 1666 59


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