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)

All filariae examined to date express a comprehensive repertoire of both cytoplasmic and secreted anti-oxidant enzymes, although significant differences exist between species and life-cycle stages. Adult Brugia malayi, Dirofilaria immitis and Onchocerca volvulus secrete CuZn superoxide dismutases, and the former two species also secrete a selenocysteine-independent glutathione peroxidase. This enzyme has been localised to the cuticular matrix of B. malayi, and the preferential reduction of fatty acid- and phospholipid hydroperoxides suggests that it may protect cuticular membranes from oxidative damage rather than directly metabolise hydrogen peroxide. Adult O. volvulus may compensate for an apparent deficiency in expression of this enzyme via a secreted variant of glutathione S-transferase. Recent studies have identified a highly expressed family of enzymes collectively termed peroxiredoxins, which most probably play an essential role in reduction of hydroperoxides. Data from cDNA cloning exercises indicate that all filarial species examined thus far express at least two peroxiredoxin variants which have been localised to diverse tissues. In-vitro studies have shown that B. malayi are particularly resistant to oxidative stress, and that the parasites do not rely solely on enzymatic mechanisms of defence. Cuticular lipids are relatively resistant to lipid peroxidation due to the low unsaturation indices of the constituent fatty acyl residues, but complete protection is afforded by the presence of alpha-tocopherol, presumably assimilated from host extracellular fluids. Brugia malayi are also relatively resistant to nitric oxide-mediated toxicity, and this may be due in part to incomplete dependence on aerobic metabolism. Little is known of potential mechanisms for detoxification of nitric oxide derivatives and adaptive responses to oxidative stress in general, and these represent goals for future research.
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PMID:Resistance of filarial nematode parasites to oxidative stress. 977 Jun 16

Electrophiles and reactive oxygen species have been implicated in the pathogenesis of many diseases. Transcription factor Nrf2 was recently identified as a general regulator of one defense mechanism against such havoc. Nrf2 regulates the inducible expression of a group of detoxication enzymes, such as glutathione S-transferase and NAD(P)H:quinone oxidoreductase, via antioxidant response elements. Using peritoneal macrophages from Nrf2-deficient mice, we show here that Nrf2 also controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system x(c)(-)) activity. The response to electrophilic and reactive oxygen species-producing agents was profoundly impaired in Nrf2-deficient cells. The lack of induction of system x(c)(-) activity resulted in the minimum level of intracellular glutathione, and Nrf2-deficient cells were more sensitive to toxic electrophiles. Several stress agents induced the DNA binding activity of Nrf2 in the nucleus without increasing its mRNA level. Thus Nrf2 regulates a wide-ranging metabolic response to oxidative stress.
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PMID:Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. 1082 56

The membrane-bound NADH dehydrogenase of an alkaliphilic Bacillus YN-1 involved in the respiratory chain exhibits reductase activity for hydrogen peroxide and cumene hydroperoxide in the presence of the 22-kDa component (AhpC) from Amphibacillus xylanus (Koyama et al. Biochem. Biophys. Res. Commun. 247, 659-662). In this study, AhpC-like polypeptide with an apparent molecular mass of 20 kDa was isolated from the cell-free extract of YN-1. The NADH dehydrogenase exhibited reductase activity for cumene hydroperoxide in the presence of the purified AhpC-like component from YN-1. It is likely that the NADH dehydrogenase is not only involved in the respiratory chain, but also functions for scavenging peroxide in the presence of its own endogenous AhpC component. The enzyme expressed in Escherichia coli as a fusion protein with glutathione S-transferase (GST) showed the NADH dehydrogenase activity as high as the native enzyme from YN-1. While the fusion protein was unable to reduce cumene hydroperoxide in the presence of AhpC-like protein from YN-1, the protein obtained by the cleavage treatment of the fusion protein to release GST exhibited the reductase activity as much as the native enzyme.
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PMID:Peroxide reductase activity of NADH dehydrogenase in the presence of an endogenous 20-kDa component of an alkaliphilic Bacillus. 1108 Mar 86

Diesel exhaust particles (DEP) induce pulmonary diseases including asthma and chronic bronchitis. Comprehensive evaluation is required to know the effects of pollutants including DEP on these and other lung diseases. Alveolar macrophages (AM) and epithelial cells are important cellular targets for pollutants such as DEP in the lung. Alveolar macrophages encounter and phagocytose DEP in the alveolar space, and their biological responses have been implicated in DEP-induced pulmonary diseases. Expression profiles of genes induced by DEP in AM will lead to better understanding of the mechanisms involved in pulmonary diseases. To characterize the effect of the DEP extract on AM systematically, we analyzed the gene expression in AM exposed to DEP extract using the Atlas Rat Toxicology Array II. The finding in cDNA microarray was further confirmed by Northern blot analysis. AM were exposed to 10 microg/ml of DEP extract for 6 h in order to elucidate early response to DEP extract in AM. Early response to DEP extract in AM may affect the alteration of gene expression in subsequent responses so that it is important to identify the alteration in early response. In this study, the transcription of 6 genes in the cDNA microarray was significantly elevated by exposure of the AM to DEP extract. These genes were heme oxygenase (HO)-1 and -2, thioredoxin peroxidase 2 (TDPX-2), glutathione S-transferase P subunit (GST-P), NAD(P)H dehydrogenase, and proliferating cell nuclear antigen (PCNA). The antioxidative enzymes such as HO, TDPX-2, GST-P, and NAD(P)H dehydrogenase may play a role in the pulmonary defense against oxidative stress caused by various pollutants including DEP. PCNA may have contributed to the repair of DNA damage and to cell proliferation caused by exposure to these pollutants. Our results suggest that cDNA microarray analysis is a useful tool to investigate the biological responses to pulmonary toxicants.
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PMID:cDNA microarray analysis of gene expression in rat alveolar macrophages in response to organic extract of diesel exhaust particles. 1201 83

Injury to motor neurons associated with mutant Cu,Zn-superoxide dismutase (SOD1)-related familial amyotrophic lateral sclerosis (FALS) results from a toxic gain-of-function of the enzyme. The mechanisms by which alterations to SOD1 elicit neuronal death remain uncertain despite intensive research effort. Analysis of the cellular proteins that are differentially expressed in the presence of mutant SOD1 represents a novel approach to investigate further this toxic gain-of-function. By using the motor neuron-like cell line NSC34 stably transfected with wild-type, G93A, or G37R mutant human SOD1, we investigated the effects of mutant human SOD1 on protein expression using proteomic approaches. Seven up-regulated proteins were identified as argininosuccinate synthase, argininosuccinate lyase, neuronal nitric-oxide synthase, RNA-binding motif protein 3, peroxiredoxin I, proteasome subunit beta 5 (X), and glutathione S-transferase (GST) Alpha 2. Seven down-regulated proteins were identified as GST Mu 1, GST Mu 2, GST Mu 5, a hypothetical GST Mu, GST Pi B, leukotriene B(4) 12-hydroxydehydrogenase, and proteasome subunit beta5i (LMP7). GST assays demonstrated a significant reduction in the total GST activity of cells expressing mutant human SOD1. Proteasome assays demonstrated significant reductions in chymotrypsin-like, trypsin-like, and post-glutamylhydrolase proteasome activities. Laser capture microdissection of spinal cord motor neurons from human FALS cases, in conjunction with reverse transcriptase-PCR, demonstrated decreased levels of mRNA encoding GST Mu 1, leukotriene B(4) 12-hydroxydehydrogenase, and LMP7. These combined approaches provide further evidence for involvement of alterations in antioxidant defenses, proteasome function, and nitric oxide metabolism in the pathophysiology of FALS.
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PMID:Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant defenses, and nitric oxide synthetic pathways. 1247 80

In this study, we report the identification of two arsenic-binding proteins from Chinese hamster ovary (CHO) cells. The crude extract derived from CHO and SA7 (arsenic-resistant CHO cells) was applied to a phenylarsine oxide-agarose affinity column, and after extensive washing, the absorbed proteins were eluted with buffers containing 20 mM 2-mercaptoethanol (2-ME) or dithiothreitol (DTT). Three differentially expressed proteins, galectin 1 (Gal-1; in the 2-ME-eluted fraction from CHO cells), glutathione S-transferase P-form (GST-P) and thioredoxin peroxidase II (TPX-II), respectively in the 2-ME- and DTT-eluted fractions from SA7 cells, were identified by partial amino acid sequence analysis after separation by SDS/PAGE. The GST-P protein has been previously shown to facilitate the excretion of sodium arsenite [As(III)] from SA7 cells. TPX II was detected predominately in SA7 cells [routinely cultured in As(III)-containing medium], but not in CHO or SA7N (a revertant of SA7 cells cultured in regular medium) cells. In contrast, Gal-1 was specifically identified in CHO and SA7N cells, but not in SA7 cells. The preferential expression of Gal-1 in CHO cells and TPX-II in SA7 cells was further illustrated by quantitative PCR analysis. The binding of Gal-1 and TPX-II with As(III) was further verified by both co-immunoprecipitation and co-elution of Gal-1 and TPX-II with As(III). It is suggested that Gal-1 and TPX-II are two proteins that serve as high-affinity binding sites for As(III) and thus both may be involved in the biological action of As(III).
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PMID:Identification of galectin I and thioredoxin peroxidase II as two arsenic-binding proteins in Chinese hamster ovary cells. 1251 79

Exposure to fine particulate materials is associated with an increase in mortality rate of cardiovascular diseases. Particles deposited in the lung may affect the vascular system both directly (leaching of soluble components from particles) and indirectly (via cytokines and mediators). The present study addressed cytotoxicity and oxidative stress potency of organic extracts of diesel exhaust particles (OE-DEP) and urban fine particles (OE-UFP) in rat heart microvessel endothelial (RHMVE) cells. The LC(50) values of OE-DEP and OE-UFP were calculated to be 17 and 34 microg/ml, respectively, suggesting that OE-DEP was more cytotoxic than OE-UFP. The viability of OE-DEP- and OE-UFP-exposed cells was ameliorated by N-acetyl-L-cysteine (NAC). The cell monolayer was exposed to 0 (control), 1, 3, and 10 microg/ml OE-DEP for 6 h and mRNA levels of antioxidant enzymes such as heme oxygenase-1 (HO-1), thioredoxin peroxidase 2 (TRPO), glutathione S-transferase P subunit (GST-P), and NADPH dehydrogenase (NADPHD) were quantitated by northern analysis. All those mRNA levels increased dose-dependently with OE-DEP and HO-1 mRNA showed the most marked response to OE-DEP. mRNA levels of those antioxidant enzymes and heat shock protein 72 (HSP72) in OE-DEP-exposed cells were higher than those of OE-UFP-exposed cells as compared at the same concentration. The transcription levels of HO-1 and HSP72 in OE-DEP- and OE-UFP-exposed cells were also reduced by NAC. Those results suggest that the organic fraction of particulate materials in the urban air has a potency to cause oxidative stress to endothelial cells and may be implicated in cardiovascular diseases through functional changes of endothelial cells.
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PMID:Oxidative-stress potency of organic extracts of diesel exhaust and urban fine particles in rat heart microvessel endothelial cells. 1269 5

Elemental mercury (Hg0) is a highly toxic chemical with increasing public health concern. Although the lung receives the highest exposure to Hg0 vapor, it is resistant to Hg0 toxicity relative to the kidney and brain. In an earlier study, exposure of rats to 4 mg Hg0 vapor/m3, 2 h per day for 10 days, did not produce pathological alterations in the lung but increased metallothionein and glutathione S-transferase in the kidney. This study was undertaken to examine pulmonary gene expression associated with Hg0 vapor inhalation. Total RNA was extracted from lung tissues of rats, previously exposed to air or Hg0 vapor, and subjected to microarray analysis. Hg0 vapor exposure increased the expression of genes encoding inflammatory responses, such as chemokines, tumor necrosis factor-alpha (TNFalpha), TNF-receptor-1, interleukin-2 (IL-2), IL-7, prostaglandin E2 receptor, and heat-shock proteins. As adaptive responses, glutathione S-transferases (GST-pi, mGST1), metallothionein, and thioredoxin peroxidase were all increased in response to Hg exposure. Some transporters, such as multidrug resistance-associated protein (MRP), P-glycoprotein, and zinc transporter ZnT1, were also increased in an attempt to reduce pulmonary Hg load. The expression of transcription factor c-jun/AP-1 and PI3-kinases was suppressed, while the expression of protein kinase-C was increased. Expression of epidermal fatty acid-binding protein was also enhanced. Real-time RT-PCR and Western blot analyses confirmed the microarray results. In summary, genomic analysis revealed an array of gene alterations in response to Hg0 vapor exposure, which could be important for the development of pulmonary adaptation to Hg during Hg0 vapor inhalation.
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PMID:Genomic analysis of the rat lung following elemental mercury vapor exposure. 1273 Jun 25

Intake of inorganic arsenic is known to cause vascular diseases as well as skin lesions and cancer in humans. We investigated the differences in cytotoxicity, uptake rate of arsenic, and gene expression of antioxidative enzymes between arsenite (As(3+))- and arsenate (As(5+))-exposed rat heart microvessel endothelial cells. As(3+) was more cytotoxic than As(5+), and LC(50) values were calculated to be 36 and 220 micro M, respectively. As(3+) (1-25 micro M) increased mRNA levels of antioxidant enzymes such as heme oxygenase-1 (HO-1), thioredoxin peroxidase 2, NADPH dehydrogenase, and glutathione S-transferase P subunit. HO-1 mRNA levels showed the most remarkable increase in response to As(3+). cDNA microarray analysis indicated that there was no prominent difference in arsenic-induced transcriptional changes between As(3+)- and As(5+)-exposed cells, when the cells were exposed to one-fourth the LC(50) concentration of arsenic (9 and 55 micro M for As(3+) and As(5+), respectively). N-acetyl- l-cysteine (NAC) reduced both the cytotoxicity of inorganic arsenic and the HO-1 mRNA level, and buthionine sulfoximine enhanced cytotoxicity of inorganic arsenic. As(3+) was taken up by the endothelial cells 6-7 times faster than As(5+), and the presence of NAC in the culture medium did not change the uptake rate of As(3+). These results suggest that the effects of NAC on arsenic-induced cytotoxicity and oxidative stress were due to the antioxidative role of non-protein thiols and not to chelation of arsenic in the culture medium. The difference in cellular uptake of arsenic between As(3+) and As(5+) appeared not to be due to the ionic charge on arsenic (at physiological pH, trivalent arsenic is neutral whereas pentavalent arsenic is negatively charged). These results suggest that the higher toxicity of As(3+) compared with that of As(5+) is probably due to the faster uptake of As(3+) by endothelial cells, and inorganic arsenic exerts its toxicity at least in part via intracellular oxidative stress.
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PMID:Difference in uptake and toxicity of trivalent and pentavalent inorganic arsenic in rat heart microvessel endothelial cells. 1279 70

Previously, we reported that the yeast cytoplasmic thiol peroxidase type II isoform (cTPx II), a member of the TSA/AhpC family, showed a very low peroxidase activity when compared with other cytoplasmic yeast isoforms, and that cTPx II mutant (cTPx II Delta) showed a severe growth retardation compared with that of the wild-type cells. To reveal the physiological function of cTPx II in yeast cell growth, we searched for proteins which react with cTPx II. In this study, we identified a novel interaction between cTPx II and CSR1p using the yeast two-hybrid system. CSR1p (SFH2p) has been known to be one member of Sec14 homologous (SFH2) proteins. SFH2p exhibits phosphatidylinositol transfer protein activity. Interestingly, we found that cTPx II selectively bound to SFH2p among the five types of SFH proteins and Sec14p. The interaction required the dimerization of cTPx II. In addition, SFH2p also specifically bound to cTPx II among the yeast thiol peroxidase isoforms. The selective interaction of the dimer form of cTPx II (the oxidized form) with SFH2p was also confirmed by glutathione S-transferase pull-down and immunoprecipitation assays. The growth retardation, clearly reflected by the length of the lag phase, of cTPx II Delta was rescued by deleting SFH2p in the cTPx II Delta strain. The SFH2 Delta strain did not show any growth retardation. In addition, the double mutant showed a higher susceptibility to oxidative stress. This finding provides the first in vivo demonstration of the specific interaction of cTPx II with SFH2p in an oxidative stress-sensitive manner and a novel physiological function of the complex of cTPx II and SFH2p.
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PMID:The protein interaction of Saccharomyces cerevisiae cytoplasmic thiol peroxidase II with SFH2p and its in vivo function. 1282 82


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