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:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resveratrol is a polyphenolic chemopreventive agent that has been shown to influence cellular redox reactions. As a systematic approach to elucidating the complex effects of resveratrol on eukaryotic cells, we studied its dose-dependent effects on the transcript levels of genes and activities of enzymes related to redox metabolism, cell cycle regulation, and apoptotic cascades in the cancer cell line A549. Glutathione peroxidase (GPx)1 mRNA levels, as well as GPx and thioredoxin reductase (TrxR) activities, were significantly increased after resveratrol treatment, whereas total glutathione concentrations decreased. Increased transcript levels were also detected for selenophosphate synthetase 2 and superoxide dismutase 2. However, mRNA levels of thioredoxin, TrxR, glutathione reductase, glutathione S-transferase, superoxide dismutase 1, and catalase were not altered. Among the 12 genes studied that are related to the cell cycle, differentiation and apoptosis, mRNA levels of six genes, including P53, FAS, and BCL2, were upregulated, while the mRNA level of survivin was reduced. The results suggest that GPx and other selenoproteins are important targets of resveratrol. Furthermore, genes supporting cell survival and differentiation, as well as genes involved in proliferation inhibition and apoptosis, are induced by resveratrol, resulting in a delicate balance that is likely to contribute to the chemopreventive effects of resveratrol.
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PMID:Resveratrol modulates mRNA transcripts of genes related to redox metabolism and cell proliferation in non-small-cell lung carcinoma cells. 1726 Oct 84

Cellular redox metabolism is considered to be involved in the pathophysiology of diseases caused by protozoal parasites such as Toxoplasma, Trypanosoma, Leishmania, and Plasmodia. Redox reactions furthermore are thought to play a major role in the action of and the resistance to some clinically used antiparasitic drugs. Interestingly, in malarial parasites, the antioxidant enzymes catalase and glutathione peroxidase are absent which indicates a crucial role of the thioredoxin system in redox control. Besides a glutathione peroxidase-like thioredoxin peroxidase and a glutathione S-transferase with slight peroxidase activity, Plasmodium falciparum (the causative agent of tropical malaria) possesses four classical peroxiredoxins: Two peroxiredoxins of the typical 2-Cys Prx class, one 1-Cys peroxiredoxin with homology to the atypical 2-Cys Prx class, and a peroxiredoxin of the 1-Cys Prx class have been identified and partially characterized In our article we give an introduction to redox-based drug development strategies against protozoal parasites and summarize the present knowledge on peroxiredoxin systems in Plasmodium.
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PMID:Peroxiredoxin systems of protozoal parasites. 1808 96

All six mammalian peroxiredoxins are expressed in the lung. Peroxiredoxin (Prx) VI is the isoform expressed at the highest level and its lung expression exceeds that for other organs. The predominant location of Prx VI is the cytosol and acidic organelles of Clara cells of the conducting airways and type II epithelial cells and macrophages in the alveoli. Prx I and VI show developmental induction of transcription at birth. PrxVI shares structural homology with other peroxiredoxins exhibiting a thioredoxin fold and a conserved catalytic Cys residue in the N-terminus of the protein. This enzyme is highly inducible by oxidative stress in both the neonatal and adult lung consistent with a role in antioxidant defense. Prx VI has several properties that distinguish its peroxidase activity from other peroxiredoxins: it can reduce phospholipid hydroperoxides in addition to other organic hydroperoxides and H2O2; the electron donor that serves to reduce the oxidized peroxidatic cysteine is not thioredoxin but GSH; instead of homodimerization, heterodimerization with pi-glutathione S-transferase is required for regeneration of the active enzyme. Prx VI also expresses a phospholipase A2 activity that is Ca2+-independent, maximal at acidic pH, and dependent on a serine-based catalytic triad and nucleophilic elbow at the surface of the protein. Models of altered Prx VI expression at the cellular, organ and whole animal levels have demonstrated that Prx VI functions as an important anti-oxidant enzyme with levels of protection that exceed those ascribed to GSH peroxidase (GPx1). The phospholipase A2 activity plays an important role in lung surfactant homeostasis and is responsible for the bulk of the degradation of internalized phosphatidylcholine and its resynthesis by the reacylation pathway. Expression of peroxiredoxins is elevated in several lung diseases including lung cancer, mesothelioma and sarcoidosis, although the mechanism for these alterations is not known. The unique properties of Prx VI enable it to play an important role in lung cell function.
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PMID:Peroxiredoxins in the lung with emphasis on peroxiredoxin VI. 1808 1

Spraying of agricultural crops with insecticides can select for resistance in nontarget insects and this may compromise the use of insecticides for the control of vector-borne diseases. The tolerance of the malaria vector, Anopheles arabiensis to deltamethrin was determined in a field population from a cotton-growing region of Northern Cameroon both prior to and midway through the 4-month period of insecticide application to the cotton crop. A 1.6-fold increase in the median knockdown time was observed. To determine whether this increased tolerance was associated with constitutively elevated levels of genes commonly associated with insecticide resistance, RNA was extracted from F1 progeny from family lines of field-caught mosquitoes and hybridized to the Anopheles gambiae detox chip. The experimental design avoided the confounding effects of colonization, and this study is the first to measure gene expression in the progeny of gravid, wild-caught mosquitoes. Several genes with antioxidant roles, including superoxide dismutases, a glutathione S-transferase and a thioredoxin-dependent peroxidase, and a cytochrome P450 showed elevated expression in mosquito families collected during the insecticide-spraying programme. These genes may constitute an important general defence mechanism against insecticides. Intriguingly, the levels of expression of these genes were strongly correlated suggesting a common regulatory mechanism.
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PMID:Pyrethroid tolerance is associated with elevated expression of antioxidants and agricultural practice in Anopheles arabiensis sampled from an area of cotton fields in Northern Cameroon. 1817 25

PICOT (protein kinase C-interacting cousin of thioredoxin) was previously shown to inhibit pressure overload-induced cardiac hypertrophy, concomitant with an increase in ventricular function and cardiomyocyte contractility. The combined analyses of glutathione S-transferase pull-down experiments and mass spectrometry enabled us to determine that PICOT directly interacts with muscle LIM protein (MLP) via its carboxyl-terminal half (PICOT-C). It was also shown that PICOT colocalizes with MLP in the Z-disc. MLP is known to play a role in anchoring calcineurin to the Z-disc in the sarcomere, which is critical for calcineurin-NFAT (nuclear factor of activated T cells) signaling. We, therefore, suggested that PICOT may affect calcineurin-NFAT signaling through its interaction with MLP. Consistent with this hypothesis, PICOT, or more specifically PICOT-C, abrogated phenylephrine-induced increases in calcineurin phosphatase activity, NFAT dephosphorylation/nuclear translocation, and NFAT-dependent transcriptional activation in neonatal cardiomyocytes. In addition, pressure overload-induced upregulation of NFAT target genes was significantly diminished in the hearts of PICOT-overexpressing transgenic mice. PICOT interfered with MLP-calcineurin interactions in a dose-dependent manner. Moreover, calcineurin was displaced from the Z-disc, concomitant with an abrogated interaction between calcineurin and MLP, in the hearts of PICOT transgenic mice. Replenishment of MLP restored the hypertrophic responses and the increase in calcineurin phosphatase activity that was inhibited by PICOT in phenylephrine-treated cardiomyocytes. Finally, PICOT-C inhibited cardiac hypertrophy to an extent that was comparable to that of full-length PICOT. Taken together, these data suggest that PICOT inhibits cardiac hypertrophy largely by negatively regulating calcineurin-NFAT signaling via disruption of the MLP-calcineurin interaction.
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PMID:PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling. 1836 59

We show that a glutathione transferase (GST) protein, which is recognised by an antibody against the muscle-specific human GSTM2-2 (hGSTM2-2), is associated with the lumen of the sarcoplasmic reticulum (SR) of cardiac muscle, but not skeletal muscle. We further show that hGSTM2-2 modifies both cardiac and skeletal ryanodine receptor (RyR) activity when it binds to the luminal domain of the RyR channel complex. The properties of hGSTM2-2 were compared with those of the calsequestrin (CSQ), a Ca(2+) binding protein also present in the lumen of the SR which, like GSTM2-2, contains a thioredoxin-fold structure and modifies RyR activity (Wei, L., Varsanyi, M., Dulhunty, A. F., Beard, N. A. (2006). The Biophysical Journal, 91, 1288-1301). The glutathione transferase activity of hGSTM2-2 is strong, while CSQ is essentially inactive. Conversely CSQ is a strong Ca(2+) binder, but hGSTM2-2 is not. The effects of luminal hGSTM2-2 on RyR activity differ from those of CSQ in that hGSTM2-2 activates RyRs by increasing their open probability and conductance and the effects are independent of luminal Ca(2+) concentration. The results suggest that GSTM2-2 can interact with specific luminal sites on the RyR complex and that the interaction is likely to be within the pore of the RyR channel. The differences between the effects of CSQ and hGSTM2-2 suggest that the thioredoxin fold is not a major determinant of the luminal actions of either protein. The results indicate that GSTM2-2 is a novel luminal regulator of the RyR channels in the heart.
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PMID:Muscle-specific GSTM2-2 on the luminal side of the sarcoplasmic reticulum modifies RyR ion channel activity. 1830 13

The detection of genes having similar expression profiles following the application of different stimuli that trigger bud break may constitute potent tools for the identification of pathways with a central role in dormancy release. We compared the effects of heat shock (HS) and hydrogen cyanamide (HC) and demonstrated that HS leads to earlier and higher bud-break levels. Changes in transcript levels of catalase, alcohol dehydrogenase and pyruvate decarboxylase were induced following both treatments. However, timing and extent of changes in transcript level differed. Changes occurred earlier in HS-treated buds and were more intense in HC-treated buds. The changes in transcript levels after both treatments were temporary. The rapid and short-lasting changes in gene expression following HS treatment correlated with the faster and higher level of bud-break that this treatment exerted. This correlation may propose that the reported molecular events are mechanistically involved in dormancy release. To test the hypothesis that temporary oxidative stress is part of the mechanism inducing dormancy release, we analyzed the effect of HS and HC treatments on the expression of ascorbate peroxidase, glutathione reductase, thioredoxin h, glutathione S-transferase and sucrose synthase genes and found that they were induced by both treatments in a similar pattern. Taken together, these findings propose that similar cellular processes might be triggered by different stimuli that lead to dormancy release, and are consistent with the hypothesis that temporary oxidative stress and respiratory stress might be part of the mechanism that leads to bud break.
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PMID:Similar mechanisms might be triggered by alternative external stimuli that induce dormancy release in grape buds. 1832 12

Human labor is characterized by dramatic physiological and structural alterations of the cervix and overlying fetal membranes, leading to myometrial activation and delivery. To investigate the potential mechanism of these changes, we performed 2D PAGE proteomic analysis on serial cervico-vaginal fluid samples obtained from women during late pregnancy and spontaneous labor. We identified 9 protein spots that were significantly altered ( p < 0.05) in association with spontaneous term labor. Eight protein spots were definitively characterized by electrospray ion-trap mass spectrometry yielding 7 different proteins: cystatin-A, interleukin-1 receptor antagonist, glutathione S-transferase P, peroxiredoxin-2, thioredoxin, copper-zinc superoxide dismutase, and epidermal fatty-acid binding protein. These proteins are involved in protease inhibition, anti-inflammatory cytokine activity, and oxidative stress defense. These findings may provide an insight into the biochemical processes and timing associated with extracellular matrix remodelling of the cervix, supracervical fetal membranes, and myometrial activation in association with spontaneous term labor. Application of these findings may lead to development of predictive biomarkers of labor onset.
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PMID:Proteomic analysis of human cervico-vaginal fluid displays differential protein expression in association with labor onset at term. 1837 36

Many proteins contain cysteines which are sensitive to oxidation. This is sometimes reversible through interaction with glutathione, glutaredoxin or thioredoxin systems making these proteins potential sensors of oxidative stress. In this study we analysed whether there was an increase in mixed disulphide bond (-S-S-) formation in the blue mussel Mytilus edulis in response to menadione. This was achieved by initially blocking reduced thiols with N-ethylmaleimide, -S-S- were then reduced with dithiothreitol (DTT) and labelled with 5-iodoacetamidofluorescein (5-IAF). Free -SHs were also labelled directly with 5-IAF. Separations were performed on 1D or 2D SDS PAGE and images analysed. There was an increase in -S-S- in response to menadione and detection of changes in oxidised proteins was easier than that of changes in the amount of reduced proteins. Protein disulphide isomerase (PDI) was labelled both as -SH and -S-S-, underlining its involvement in the redox status of the animal. A glutathione transferase (GST P1-1) forms an inter-chain disulphide bridge in response to menadione.
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PMID:Effects of oxidative stress on protein thiols and disulphides in Mytilus edulis revealed by proteomics: actin and protein disulphide isomerase are redox targets. 1839 26

Emerging evidence indicates that Nox (NADPH oxidase) 1-generated ROS (reactive oxygen species) play critical regulatory roles in various cellular processes, yet little is known of direct targets for the oxidase. In the present study we show that one of the proteins selectively oxidized in response to Nox1-generated ROS was ERp72 (endoplasmic reticulum protein 72 kDa) with TRX (thioredoxin) homology domains. Oxidation of ERp72 by Nox1 resulted in an inhibition of its reductase activity. EGF treatment of cells stimulated the Nox1 activity and the activated Nox1 subsequently mediated EGF-induced suppression of the ERp72 reductase activity. Co-immunoprecipitation, GST (glutathione transferase) pulldown assays and mutational analysis, indicated that Nox1 associates with ERp72, which involves its N-terminus encompassing a Ca(2+)-binding site and the first TRX-like motif. Furthermore, confocal microscopy showed co-localization between Nox1 and ERp72 at the plasma membrane. These results suggest that Nox1 functionally associates with ERp72, regulating redox-sensitive signalling pathways in a cellular context.
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PMID:A possible biochemical link between NADPH oxidase (Nox) 1 redox-signalling and ERp72. 1862 May 48


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