Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.3 (glutathione synthetase)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate Saccharomyces cerevisiae physiology during growth on the conditionally toxic triose dihydroxyacetone (DHA), protein expression was studied in strains overexpressing either of the two dihydroxyacetone kinase isogenes, DAK1 or DAK2, that grow well utilizing DHA as a carbon and energy source. DHA metabolism was found mostly similar to ethanol utilization, involving a strong component of glucose derepression, but also involved DHA-specific regulatory changes. A specific and strong (10- to 30-fold induction of formaldehyde dehydrogenase, Fdhlp, indicated activation of the formaldehyde dissimilation pathway in DHA medium. The importance of this pathway was further supported by impaired adaptation to DHA growth and DHA survival in a glutathione-dependent formaldehyde dehydrogenase (SFA1) deletion mutant. Glutathione synthase (GSH1) deletion led to decreased DHA survival in agreement with the glutathione cofactor requirement for the SFA1-encoded activity. DHA toxicity did, however, not solely appear related to formaldehyde accumulation, because SFA1 overexpression only enhanced formaldehyde but not DHA tolerance. In further agreement with a low DHA-to-formaldehyde flux, GSH supplements in the low microM range also fully suppressed the DHA sensitivity of a gsh1Delta strain. Under growth reduction on high (100 mM) DHA medium we report increased levels of advanced glycation end-product (AGE) formation on total protein. Under these high-DHA conditions expression of several stress-related proteins, e.g. a heat-shock protein (Hsp104p) and the oxidative stress indicator, alkyl hydroperoxide reductase (Ahp1p) was also found induced. However, hallmark determinants of oxidative stress tolerance (e.g. YAP1, SKN7, HYR1/GPX3 and SOD2) were redundant for DHA tolerance, thus indicating mechanisms of DHA toxicity largely independent of central oxidative stress defence mechanisms. We conclude that mechanisms for DHA growth and detoxification appear complex and that the evolutionary strive to minimize detrimental effects of this intracellular metabolite links to both formaldehyde and glutathione metabolism.
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PMID:Dihydroxyacetone detoxification in Saccharomyces cerevisiae involves formaldehyde dissimilation. 1667 4

5-Oxoprolinuria is primarily associated with inborn errors of the gamma-glutamyl cycle. In addition, transient 5-oxoprolinuria has been reported to occur in a variety of conditions, such as prematurity and malnutrition, and during medication. We report an unusual case of permanent 5-oxoprolinuria. The patient presented 3 days after birth with acidosis, and metabolic screening revealed massive excretion of 5-oxoproline. Following recovery, growth and psychomotor development were normal, but 5-oxoprolinuria persisted. Primary defects in the gamma-glutamyl cycle were ruled out since glutathione synthase and 5-oxoprolinase activities were normal. All known secondary causes of 5-oxoprolinuria were also excluded, leaving the basis of the permanent 5-oxoprolinuria in this patient unresolved.
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PMID:Persistent 5-oxoprolinuria with normal glutathione synthase and 5-oxoprolinase activities. 1683 Feb 60

Folate deficiency increases neuronal oxidative damage and potentiates the deleterious effects of apolipoprotein E (ApoE) deficiency. Mice lacking ApoE (ApoE -/- mice) upregulate the expression and activity of another enzyme, glutathione synthase (GS), when deprived of folate, in an apparent attempt to compensate for increased oxidative damage. Herein, we examined the influence of ApoE and folate deficiency on expression and activity of several enzymes of the methionine cycle. Expression and activity of methylene tetrahydrofolate reductase was increased in the order ApoE +/+ < ApoE +/- < ApoE -/- in response to folate deprivation. Expression of cystathione beta synthase followed a similar pattern. By contrast, expression and activity of methionine synthase decreased following folate deprivation in the order ApoE +/+ < ApoE +/- < ApoE -/-. These studies demonstrate that folate deficiency induces compensatory regulation of methionine cycle genes, and that these effects are potentiated by ApoE deficiency in a gene-dosage manner. They further support the notion that latent genetic deficiencies, including those of methionine cycle, may contribute to Alzheimer's disease, especially in concert with age-related nutritional deficiencies.
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PMID:Expression and activity of methionine cycle genes are altered following folate and vitamin E deficiency under oxidative challenge: modulation by apolipoprotein E-deficiency. 1691 Jan 66

In most organisms, glutathione (GSH) is synthesized by the sequential action of distinct enzymes, gamma-glutamylcysteine synthetase (gamma-GCS) and GSH synthetase (GS). In Streptococcus agalactiae, GSH synthesis is catalyzed by a single enzyme, gamma-glutamylcysteine synthetase-glutathione synthetase (gamma-GCS-GS). The N-terminal sequence of gamma-GCS-GS is similar to Escherichia coli gamma-GCS, but the C-terminal sequence is an ATP-grasp domain more similar to d-Ala, d-Ala ligase than to any known GS. In the present studies, C-terminally and N-terminally truncated constructs were characterized in order to define the limits of the gamma-GCS and GS domains, respectively. Although WT gamma-GCS-GS is nearly uninhibited by GSH (K(i) approximately 140 mM), shorter gamma-GCS domain constructs were unexpectedly found to be strongly inhibited (K(i) approximately 15 mM), reproducing a physiologically important regulation seen in monofunctional gamma-GCS enzymes. Because studies with E. coli gamma-GCS implicate a flexible loop region in GSH binding, chimeras of S. agalactiae gamma-GCS-GS were made containing gamma-GCS domain flexible loop sequences from Enterococcus faecalis and Pasteurella multocida gamma-GCS-GS, isoforms that are inhibited by GSH. Inhibition remained S. agalactiae-like (i.e., very weak). C-Terminal constructs of gamma-GCS-GS have GS activity (0.01-0.04% of WT), but proper folding and significant GS activity required a covalently linked gamma-GCS domain. In addition, site-directed mutants in the middle region of the gamma-GCS-GS sequence established that GS activity depends on residues in a region that is also part of the gamma-GCS domain. Our results provide new insights into the structure of gamma-GCS-GS and suggest gamma-GCS-GS evolved from a monomeric gamma-GCS that became C-terminally fused to a multimeric ATP-grasp protein.
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PMID:Gamma-glutamylcysteine synthetase-glutathione synthetase: domain structure and identification of residues important in substrate and glutathione binding. 1693 98

S-Adenosylmethionine decarboxylase (SAMDC) is a key enzyme for the biosynthesis of spermidine. SAMDC-suppressed HL-60 cells overproduced intracellular reactive oxygen species (ROS), which led to cell growth defect and partial cell death. ROS overproduction was caused by a decrease of the total glutathione (GSH) and the ratio of reduced to oxidized GSH, and by an increase of the intracellular iron uptake. When analyzed by real-time polymerase chain reaction, the transcripts of the genes involved in the GSH synthesis (gamma-glutamyl cysteine synthetase, GSH synthetase), as well as the gene of the GSH-reducing enzyme (NADP+-dependent isocitrate dehydrogenase), were decreased dramatically in these cells. DNA-repairing genes (ATM, PARP, RAD51 and MSH2) also were not activated transcriptionally. In these situations, excessive ROS induced severe DNA damage, which could not be repaired, and ultimately led the cells to a spontaneous cell death or an early senescence state. For such cells, gamma-radiation and cisplatin, which are direct DNA-damaging agents, were very effective for promoting cell death.
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PMID:S-Adenosylmethionine decarboxylase partially regulates cell growth of HL-60 cells by controlling the intracellular ROS level: Early senescence and sensitization to gamma-radiation. 1706 47

The glutathione S-transferase (GST) family of genes encode for detoxification enzymes that protect against reactive oxygen species and influence host susceptibility to carcinogens, including tobacco smoke. It has not been determined whether isoenzyme GST-pi or glutathione synthase (GSH2) expression by tumor cells bears a relationship to survival. A total of 201 non-small cell lung cancers (NSCLC) with long-term follow-up were immunostained with antibodies to GST-pi and GSH2 using standard immunostaining techniques. Results were graded semiquantitatively using a scale of 0 to 3 (0 < or = 10%; 1 = 10%-50%; 2 = 51%-80%; 3 > or = 80%) for both nuclear and cytoplasmic staining. Results were correlated with patient survival using Kaplan-Meier analysis. Nuclear staining with GST-pi in greater than 10% of the cells was closely associated with decreased survival (P = .02) in stage I and II squamous cell carcinomas (n = 40). Cytoplasmic staining showed a similar trend that did not reach statistical significance. No significant correlation between GST-pi staining and survival was determined for other histologic types of NSCLC. Cytoplasmic GSH2 staining in greater than 80% of tumor cells was associated with a trend toward improved survival for stage I adenocarcinoma (P = .08) but did not show a relationship to survival for other histologic types of NSCLC. GST-pi expression predicts prognosis in stage I and II squamous cell lung carcinoma, and GSH2 expression may indicate better survival in early stage adenocarcinoma of the lung. Manipulation of GST-pi and GSH2 may be a potential basis for treatment of some NSCLC.
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PMID:Expression of glutathione S-transferase pi and glutathione synthase correlates with survival in early stage non-small cell carcinomas of the lung. 1723 69

Myeloid-derived suppressor cells (MDSC) play an important role in tumor escape by suppressing T-cell responses. MDSC represent a group of cells of myeloid lineage at different stages of differentiation. Increased arginase activity and production of reactive oxygen species (ROS) are among the main functional characteristics of these cells. Recent studies have shown that all-trans retinoic acid (ATRA) had a potent activity in eliminating MDSC in cancer patients and in tumor-bearing mice. ATRA differentiates these cells into mature myeloid cells. However, the mechanism of this effect is unclear. Here, we have shown that ATRA dramatically and specifically up-regulated gene expression and protein level of glutathione synthase (GSS) in MDSC. This resulted in accumulation of glutathione (GSH) in these cells, observed in both mice and cancer patients. Blockade of GSH synthesis cancelled the effect of ATRA on MDSC. Accumulation of GSH in these cells using N-acetyl-L-cysteine mimicked the effect of ATRA on MDSC differentiation. Analysis of potential mechanisms of ATRA effect on GSS revealed that ATRA regulates its expression not by directly binding to the promoter but primarily via activation of extracellular signal-regulated kinase 1/2. Thus, ATRA induced differentiation of MDSC primarily via neutralization of high ROS production in these cells. This novel mechanism involves specific up-regulation of GSS and accumulation of GSH and could be used in developing and monitoring therapeutic application of ATRA.
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PMID:Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. 1800 48

Reduced glutathione (L-gamma-glutamyl-L-cysteinyl-glycine, GSH) is the prevalent low-molecular-weight thiol in mammalian cells. It is formed in a two-step enzymatic process including, first, the formation of gamma-glutamylcysteine from glutamate and cysteine, by the activity of the gamma-glutamylcysteine synthetase; and second, the formation of GSH by the activity of GSH synthetase which uses gamma-glutamylcysteine and glycine as substrates. While its synthesis and metabolism occur intracellularly, its catabolism occurs extracellularly by a series of enzymatic and plasma membrane transport steps. Glutathione metabolism and transport participates in many cellular reactions including: antioxidant defense of the cell, drug detoxification and cell signaling (involved in the regulation of gene expression, apoptosis and cell proliferation). Alterations in its concentration have also been demonstrated to be a common feature of many pathological conditions including diabetes, cancer, AIDS, neurodegenerative and liver diseases. Additionally, GSH catabolism has been recently reported to modulate redox-sensitive components of signal transduction cascades. In this manuscript, we review the current state of knowledge on the role of GSH in the pathogenesis of human diseases with the aim to underscore its relevance in translational research for future therapeutic treatment design.
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PMID:The central role of glutathione in the pathophysiology of human diseases. 1815 46

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

Intestinal commensals are potential important contributors to the etiology of sporadic colorectal cancer, but mechanisms by which bacteria can initiate tumors remain uncertain. Herein, we describe mechanisms that link Enterococcus faecalis, a bacterium known to produce extracellular superoxide, to the acute induction of chromosomal instability. Immortalized human and nontransformed murine colonic epithelial cells, along with a mouse colonic ligation model, were used to assess the effect of E. faecalis on genomic DNA stability and damage. We found that this human intestinal commensal generated aneuploidy, tetraploidy, and gammaH2AX foci in HCT116, RKO, and YAMC cells. In addition, direct exposure of E. faecalis to these cells induced a G2 cell cycle arrest. Similar observations were noted by exposing cells to E. faecalis-infected macrophages in a dual-chamber coculture system for detecting bystander effects. Manganese superoxide dismutase, catalase, and tocopherols attenuated, and caffeine and inhibitors of glutathione synthase exacerbated, the aneugenic effects and linked the redox-active phenotype of this intestinal commensal to potentially transforming events. These findings provide novel insights into mechanisms by which E. faecalis and intestinal commensals can contribute to cellular transformation and tumorigenesis.
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PMID:Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect. 1904 72


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