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)

Auranofin, an oral chrysotherapeutic agent effective in the treatment of rheumatoid arthritis (RA), was found to be a potent, noncytotoxic inhibitor of IgG-RF immune complex-induced lysosomal enzyme release (LER) from human leukocytes. At a concentration of 1 microg Au/ml (5 microM), auranofin produced a marked reduction in beta-glucuronidase (100%), acid phosphatase (88%), and lysozyme (72%) release. In contrast, gold sodium thiosulfate (GST, an injectable gold compound) had no inhibitory activity on LER at equivalent gold concentrations (i.e., 1 microg Au/ml) and only modest activity (less than 36% inhibition) at concentrations as high as 40 microg Au/ml. The 50% inhibitory dose (LD50) of auranofin on LER was calculated to be 3-4 microM (0.6-0.8 microg Au/ml). Blood gold levels in auranofin-treated RA patients were found to be within the range required for in vitro inhibition of LER, and correlated with decreases in IgG, RF titers, and IgG-RF immune-complex formation in vitro. These results suggest that the therapeutic action of auranofin may be caused, at least in part, by inhibition of LER and/or decreases in immune-complex formation.
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PMID:Effect of auranofin, a new antiarthritic agent, on immune complex-induced release of lysosomal enzymes from human leukocytes. 10 28

The effect o 4 weeks dietary administration of the hormone dehydroepiandrosterone (DHEA) on enzyme and morphological phenotype of focal lesions previously induced by dimethylaminoazobenzene (DAB) treatment was investigated in Sprague-Dawley rats. In contrast to the DAB-alone livers where large numbers of glycogen-storing, mixed cell nodules homogeneously positive for glutathione S-transferase P form (GST-P) were apparent, DHEA treated animals were characterized by significantly fewer, more heterogeneous lesions, in some cases demonstrating increased amphophilia and structured basophilia. The enhanced heterogeneity, in some ways reminiscent of that reported earlier for 'reversibility' or 'remodelling' of rapidly induced nodular lesions, was associated with increased catalase (CAT), acid phosphatase (AP) and glucose-6- phosphatase (G6Pase) and decreased glycogen contents and phosphorylase (PHO) activity in both nodules and background parenchyma. Glucose-6-phosphatase (G6PD) activity was elevated irregularly focal lesions also demonstrating a heterogeneous reaction. The experimental data suggest two separate effects of the hormone treatment the first involving modulation of the usual altered phenotype of preneoplastic lesions with a shift towards 'tigroid' cell character and the second, similar to that reported earlier for rapidly induced nodules, involving enhanced phenotypic instability and leading to reduction in numbers.
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PMID:Modulating influence of dehydroepiandrosterone administration on the morphology and enzyme phenotype of dimethylaminoazobenzene-induced hepatocellular foci and nodules. 290 89

Male Sprague-Dawley rats were investigated after N-nitrosomorpholine (NNM) treatment with concomitant and subsequent administration of dehydroepiandrosterone (DHEA) for development of pre-neoplastic and neoplastic liver lesions. In addition to clear, acidophilic, mixed cell and basophilic foci, a hitherto undescribed lesion type demonstrating a unique morphological and histochemical phenotype was observed in animals receiving both NNM and DHEA. The cells of the majority of these lesions for which we propose the designation amphophilic foci were characterized by increased granular acidophilia and randomly scattered cytoplasmic basophilia. Histochemically, reduced glycogen content and elevated activity of glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), acid phosphatase (AP), succinate dehydrogenase (SDH) and catalase (CAT) were evident. The lack of gamma-glutamyl transpeptidase (GGT) or glutathione S-transferase placental form (GST-P) in foci of this type allowed clear differentiation from other NNM-induced focal lesions while suggesting certain similarities to pre-neoplastic cells induced by hypolipidemic agents. Similar enzyme histochemical patterns were characteristic for foci and later appearing nodules (adenomas) composed of amphophilic/tigroid cells the basophilic material of which was increased and frequently arranged in long striped bands. DHEA treatment, while not itself inducing any preneoplastic foci, was thus associated with altered phenotypic expression of foci and adenomas generated by NNM.
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PMID:Enzyme histochemical and morphological phenotype of amphophilic foci and amphophilic/tigroid cell adenomas in rat liver after combined treatment with dehydroepiandrosterone and N-nitrosomorpholine. 296 25

The PHO81 gene is thought to encode an inhibitor of the negative regulators (Pho80p and Pho85p) in the phosphatase (PHO) regulon. Transcription of PHO81 is regulated by Pi signals through the same PHO regulatory system. Elimination of the PHO81 promoter or its substitution by the GAL1 promoter revealed that stimulation of the PHO regulatory system requires both increased transcription of PHO81 and a Pi starvation signal. The predicted Pho81p protein contains 1,179 amino acids (aa) and has six repeats of an ankyrin-like sequence in its central region. The minimum amino acid sequence required for Pho81p function was narrowed down to a 141-aa segment (aa 584 to 724), which contains the fifth and sixth repeats of the ankyrin-like motif. The third to sixth repeats of the ankyrin-like motif of Pho81p have significant similarities to that of p16INK4, which inhibits activity of the human cyclin D-CDK4 kinase complex. Deletion analyses revealed that the N- and C-terminal regions of Pho81p behave as negative and positive regulatory domains, respectively, for the minimal 141-aa region. The negative regulatory activity of the N-terminal domain was antagonized by a C-terminal segment of Pho81p supplied in trans. All four known classes of PHO81c mutations that show repressible acid phosphatase activity in high-Pi medium affect the N-terminal half of Pho81p. An in vitro assay showed that a glutathione S-transferase-Pho81p fusion protein inhibits the Pho85p protein kinase. Association of Pho81p with Pho85p or with the Pho80p-Pho85p complex was demonstrated by the two-hybrid system.
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PMID:Functional domains of Pho81p, an inhibitor of Pho85p protein kinase, in the transduction pathway of Pi signals in Saccharomyces cerevisiae. 782 64

ABO blood groups; serum proteins, including transferring (Tf), group-specific component (Gc), proteinase inhibitor (PI), and haptoglobin (Hp); and erythrocytic enzymes, including acid phosphatase (ACP1) and phosphoglucomutase (PGM1), were studied in two ethnic groups from the Marii EI Republic-Highland and Meadow Mari. The size of populations examined were 111 and 140 individuals, respectively. Data on frequency distribution of phenotypes and genes are reported, and the two populations are compared with respect to allelic frequency. To assess the subdivision of the population, GST was used. Its value was 0.0041.
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PMID:[Population genetic characteristics of highland and meadow Mari. Genetic markers]. 875 68

Obtaining high quality protein crystals remains a rate-limiting step in the determination of three-dimensional X-ray structures. A frequently encountered problem in this respect is the high or heterogeneous carbohydrate content of many eukaryotic proteins. A number of reports have demonstrated the use of enzymatic deglycosylation in the crystallization of certain glycoproteins. Although this is an attractive tool, there are some problems that hinder the more widespread use of glycosidases in crystallization. First, commercially available glycosidases are relatively expensive, which virtually prohibits their use on a large scale. Second, the glycosidase must be removed from the glycoprotein of interest following deglycosylation, which is not always straightforward. To circumvent these problems we have cloned the two most generally useful glycosidases, peptide-N-glycosidase F and endoglycosidase F1 from Flavobacterium meningosepticum, as fusion proteins with glutathione S-transferase. The fusion not only allows rapid purification of these enzymes from Escherichia coli cell extracts, but also permits rapid removal from target proteins following deglycosylation. We have used these enzymes to obtain crystals of phytase from Aspergillus ficuum and acid phosphatase from Aspergillus niger and to obtain a new crystal form of recombinant human renin.
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PMID:Deglycosylation of proteins for crystallization using recombinant fusion protein glycosidases. 897 70

VH (heavy-chain variable region) and VL (light-chain variable region) genes were amplified by PCR from hybridomas producing MAb-11 and MAb-18 which inhibited Japanese radish acid phosphatase. Nucleotide sequencing of the V genes demonstrates that the MAbs contained similar VH and identical VL domains. Initially, the VH and VL genes were expressed in Escherichia coli as single-chain Fv (ScFv) fragments. Fragments ScFv-11 and ScFv-18, named for MAb-11 and MAb-18, respectively, inhibited the enzyme activity to the same extent as the intact MAbs. Both of the antibody fragments widely cross-reacted with other phosphatases, including some phosphomonoesterases and phosphodiesterases from different sources. ScFv-18 also inhibited acid phosphatase from a different origin, but stimulated the activity of alkaline phosphatase from calf intestine. The PCR-amplified VH and VL genes were subsequently expressed separately in Escherichia coli as fusion products with glutathione S-transferase. The fusion proteins had little effect on Japanese radish acid phosphatase. Furthermore, a large number of recombinant ScFv fragments specific to the acid phosphatase were generated by using a bacteriophage expression system and a mouse ScFv gene library. These ScFv fragments had a range of effects on the enzyme activity, including inhibition, stimulation, and none. Among them, an ScFv fragment, designated ScFv-G7, inhibited more strongly than ScFv-11 and ScFv-18.
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PMID:Antibody fragments as inhibitors of Japanese radish acid phosphatase. 969 84

In order to understand the pulmonary toxicity of ultrafine titanium dioxide (UF-TiO2) particles, various biochemical and chemical parameters were assayed in rat alveolar macrophages (AMs) and cell-free lavage fluid. Single intratracheal exposure of UF-TiO2 (2 mg per rat) caused cytotoxicity to pulmonary AMs. An increase in the population of AMs could be observed, followed by increased activities of lactate dehydrogenase and acid phosphatase in cell-free lavage fluid. In addition, AMs showed an adaptive response because the activities of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione S-transferase were increased in these cells. However, this enhancement of antioxidant enzymes could not diminish the enhanced lipid peroxidation and increased rate of hydrogen peroxide generation. The level of glutathione remained decreased in UF-TiO2-exposed rat AMs. The data suggest that the induction of antioxidant enzymes by these cells for self-protection is not sufficient to cope against the toxic action of UF-TiO2, which may lead to oxidative stress.
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PMID:Cytotoxicity, pro-oxidant effects and antioxidant depletion in rat lung alveolar macrophages exposed to ultrafine titanium dioxide. 980 29

Fc receptors modulate inflammatory processes, including phagocytosis, serotonin and histamine release, superoxide production, and secretion of cytokines. Aggregation of FcgammaRIIa, the low-affinity receptor for monomeric IgG, activates nonreceptor protein tyrosine kinases such as Lyn, Hck, and Syk, potentially driving the phosphorylation of the downstream adaptor proteins, including Cbl and/or Nck. Previous work from our laboratory using interferon-gamma-differentiated U937 (U937IF) myeloid cells investigated mechanisms which regulate Fcgamma receptor-induced assembly of adaptor complexes. Herein we report that FcgammaRII receptor signaling in U937IF and HEL cells involves Cbl and Nck, suggesting that Cbl-Nck interactions may link FcgammaRII to downstream activation of Pak kinase. FcgammaRII crosslinking induced the phosphorylation of Cbl and Nck on tyrosine. The alphaCbl immunoprecipitations revealed constitutive binding of Nck and Grb2 to Cbl and FcgammaRII-inducible binding of CrkL to Cbl. The interactions of Cbl with Nck and CrkL were phosphorylation dependent since dephosphorylation of cellular proteins with potato acid phosphatase abrogated binding. GST-Nck fusion protein pulldown experiments show that Cbl and Pak1 bind to the second SH3 domain of Nck. A specific Src inhibitor, PP1, was shown to completely abrogate the FcgammaR-induced superoxide response, correlating with a decrease in Cbl and Nck tyrosine phosphorylation. Our results provide the first evidence that Src is required for FcgammaR activation of the respiratory burst in myeloid cells and suggest that Cbl-Nck, Cbl-Pak1, and Nck-Pak1 interactions may regulate this response.
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PMID:Characterization of Cbl-Nck and Nck-Pak1 interactions in myeloid FcgammaRII signaling. 985 74

Proliferation in the setting of longstanding chronic inflammation appears to predispose to carcinoma in the liver, large bowel, urinary bladder, and gastric mucosa. Focal prostatic atrophy, which is associated with chronic inflammation, is highly proliferative (Ruska et al, Am J Surg Pathol 1998, 22:1073-1077); thus the focus of this study was to more fully characterize the phenotype of the atrophic cells to assess the feasibility of the proposal that they may be targets of neoplastic transformation. The pi-class glutathione S-transferase (GSTP1), a carcinogen-detoxifying enzyme, is not expressed in >90% of prostate carcinomas (CaPs). GSTP1 promoter hypermethylation, which appears to permanently silence transcription, is the most frequently detected genomic alteration in CaP (Lee et al, Proc Natl Acad Sci USA 1994, 91:11733-11737; >90% of cases). In high-grade prostatic intraepithelial neoplasia (PIN), this alteration is present in at least 70% of cases (Brooks et al, Cancer Epidemiol Biomarkers Prev, 1998, 7:531-536). Although normal-appearing prostate secretory cells rarely express GSTP1, they remain capable of expression, inasmuch as GSTP1 promoter hypermethylation is not detected in normal prostate. Fifty-five lesions from paraffin-embedded prostatectomy specimens (n = 42) were stained for GSTP1, using immunohistochemistry. Adjacent sections were stained for p27(Kip1), Ki-67, androgen receptor (AR), prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), Bcl-2, and basal cell-specific cytokeratins (34betaE12). With normal prostate epithelium as the internal standard, staining was scored for each marker in the atrophic epithelium. The lesions showed two cell types, basal cells staining positive for 34betaE12, and atrophic secretory-type cells staining weakly negative for 34betaE12. All lesions showed elevated levels of Bcl-2 in many of the secretory-type cells. All lesions had an elevated staining index for the proliferation marker Ki-67 in the secretory layer and decreased expression of p27(Kip1), a finding reminiscent of high-grade PIN (De Marzo et al, Am J Pathol 1998, 153:911-919). Consistent with partial secretory cell differentiation, the luminal cells showed weak to moderate staining for androgen receptor and the secretory proteins PSA and PSAP. All atrophic lesions showed elevated GSTP1 expression in many of the luminal secretory-type cells. Because all lesions are hyperproliferative, are associated with inflammation, and have the distinct morphological appearance recognized as prostatic atrophy, we suggest the term "proliferative inflammatory atrophy" (PIA). Elevated levels of GSTP1 may reflect its inducible nature in secretory cells, possibly in response to increased electrophile or oxidant stress. Elevated Bcl-2 expression may be responsible for the very low apoptotic rate in PIA and is consistent with the conclusion that PIA is a regenerative lesion. We discuss our proposal to integrate the atrophy and high-grade PIN hypotheses of prostate carcinogenesis by suggesting that atrophy may give rise to carcinoma either directly, as previously postulated, or indirectly by first developing into high-grade PIN.
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PMID:Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. 2017 14


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