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)

Both soya bean flakes (SBF) and liquorice root extract (LRE) have previously been reported to have anticarcinogenic properties, which have been thought to be related to an increased activity of specific enzymes responsible for the detoxification of chemical carcinogens. 30- and 90-day studies were conducted in male B6C3F1 mice to determine which, if any, of several detoxification enzymes are induced by SBF or LRE. Mice fed 8 and 25% LRE showed a variety of adverse clinical signs, poor weight gain and 30% mortality. Significant increases in liver:body weight ratios were observed in both the SBF and LRE groups. No significant treatment-related gross autopsy findings were observed in any of the SBF groups. A number of abnormalities were observed in the LRE groups, including lesions of the kidney, liver, spleen and thymus. Liver samples from the 90-day study were analysed for 7-ethoxycoumarin O-deethylase (7-ECOD), benzo[a]pyrene hydroxylase (BPH), superoxide dismutase (SOD), glutathione S-transferase (GST) and UDP-glucuronyl transferase (UDPGT) at 90 days, and at an interim 30-day autopsy. No treatment-related increases were observed for BPH or SOD. Both SBF and LRE induced modest increases in UDPGT activity. SBF induced modest increases in GST activity, but LRE decreased this activity. 7-ECOD activity was significantly increased by LRE and decreased by SBF. Samples from a 30-day study in which both LRE and SBF were administered at various dose levels were examined for UDPGT activity; all dose groups showed decreases in UDPGT activity relative to controls. The results suggest that both SBF and LRE may alter the activities of specific enzymes involved in the detoxification of chemical carcinogens; however, the combination of these two foodstuffs may not produce an additive effect in B6C3F1 mice.
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PMID:Effects of soya bean flakes and liquorice root extract on enzyme induction and toxicity in B6C3F1 mice. 850 19

Previous studies have shown that the mRNA encoding the Na+/Cl(-)-dependent "orphan" transporter Rxt1 is expressed exclusively in the central nervous system (CNS). In the present study, specific antibodies were raised in rabbits for the detailed mapping of this transporter in the rat. The C-terminal part of Rxt1 was fused with glutathione-S-transferase (Rxt1ct-GST) and the resulting fusion protein was used as antigen. The specificity of the antiserum toward Rxt1 was confirmed by immunofluorescent, Western blot, and immunoautoradiographic experiments. In cerebral cortex membranes, Rxt1-like material recognized by the antiserum is a glycosylated protein of 97-116 kDa. This protein was the most abundant in the caudate-putamen, followed, in decreasing order, by the cerebral cortex approximately hippocampus > cerebellum > brainstem > spinal cord. In contrast, no immunoreactive material could be detected in peripheral tissues (tongue, thymus, heart, lung, spleen, kidney, adrenals, liver, skeletal muscle, intestine, testis). Immunoautoradiographic labeling with affinity-purified anti-Rxt1ct-GST antibodies showed high levels of Rxt1-like material in the olfactory bulb, cerebral cortex, striatal complex, hippocampal formation, superior layer of the anterior colliculus, cortex, and deep nuclei in the cerebellum. The regional distribution of Rxt1-like material generally matched that of GABAergic and glutamatergic projections in agreement with previous in situ hybridization data.
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PMID:Immunolabeling of the Na+/Cl(-)-dependent "orphan" transporter Rxt1 in the rat central nervous system. 858 11

The cDNA of a novel protein kinase (referred to as SNRK) was isolated from a rat fat cell cDNA library with a probe generated by a cloning approach based on the polymerase chain reaction. The encoded polypeptide (746 amino acids, Mr=81627) contains all conserved subdomains characteristic of the protein serine/threonine kinase family. A recombinant fusion protein with glutathione S-transferase catalysed autophosphorylation as well as phosphorylation of histone, confirming that SNRK has indeed protein kinase activity. By Northern blot hybridization, a 5-kb mRNA was detected in brain, heart, fat cells, intestine, testis, ovary, adrenal gland and thymus. In 3T3-L1 cells. SNRK was specifically expressed in the differentiated, adipocyte-like phenotype, whereas its mRNA was not detected in fibroblasts. Sequence comparisons of its catalytic domain relate SNRK to the SNF1 family of protein kinases. The noncatalytic domain comprises several intriguing structural features, including a glycine-rich region, two PEST sequences, and a bipartite nuclear localization signal which is preceded by a stretch of ten consecutive acidic residues. This part of the sequence exhibits no extended similarity with other proteins. In addition, we detected a high degree of sequence similarity with other SNF1-related proteinases in a small region (30-35 amino acids) flanking the C-terminus of the catalytic domain. This domain (designated the SNH domain) appears to define the subfamily of SNF1-related protein kinases and might represent a new type of regulatory domain of protein kinases.
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PMID:Molecular cloning and characterization of a novel mammalian protein kinase harboring a homology domain that defines a subfamily of serine/threonine kinases. 865 23

Interferon gamma is a pleiotropic cytokine that regulates many immune functions. We have identified a novel protein, inducibly expressed GTPase (IGTP), whose expression was regulated by interferon gamma in macrophages. In mouse RAW 264.7 macrophages, IGTP mRNA levels were almost undetectable but increased within 1 h of exposure to interferon gamma, peaked at very high levels within 3 h, and remained at high levels to at least 48 h; pretreatment of the cells with cycloheximide blocked the majority of mRNA accumulation. In the mouse, the mRNA was highly expressed in thymus, spleen, lung, and small intestine. Using interspecific backcross analysis, the Igtp gene was mapped to mouse chromosome 11. The IGTP cDNA encoded a putative polypeptide of Mr 48,507 and pI 7.79 that contained three consensus GTP binding motifs, GXXXXGK(S/T), DXXG, and NTKXD. Both IGTP that had been immunoprecipitated from RAW cells and a glutathione S-transferase IGTP fusion protein were able to convert GTP to GDP in vitro. Subcellular protein fractionation and Western blotting localized IGTP to the cytosol of RAW cells. In addition, the protein was homologous to proteins encoded by three previously cloned cDNAs, IRG-47, TGTP/Mg21, and LRG-47, and thus may be representative of a new family of interferon gamma-regulated GTPases.
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PMID:Identification of a novel GTPase, the inducibly expressed GTPase, that accumulates in response to interferon gamma. 870 76

The Gfi-1 proto-oncogene encodes a zinc finger protein with six C2H2-type, C-terminal zinc finger motifs and is activated by provirus integration in T-cell lymphoma lines selected for interleukin-2 independence in culture and in primary retrovirus-induced thymomas. Gfi-1 expression in adult animals is restricted to the thymus, spleen, and testis and is enhanced in mitogen-stimulated splenocytes. In this report, we show that Gfi-1 is a 55-kDa nuclear protein that binds DNA in a sequence-specific manner. The Gfi-1 binding site, TAAATCAC(A/T)GCA, was defined via random oligonucleotide selection utilizing a bacterially expressed glutathione S-transferase-Gfi-1 fusion protein. Binding to this site was confirmed by electrophoretic mobility shift assays and DNase I footprinting. Methylation interference analysis and electrophoretic mobility shift assays with mutant oliginucleotides defined the relative importance of specific bases at the consensus binding site. Deletion of individual zinc fingers demonstrated that only zinc fingers 3, 4, and 5 are required for sequence-specific DNA binding. Potential Gfi-1 binding sites were detected in a large number of eukaryotic promoter-enhancers, including the enhancers of several proto-oncogenes and cytokine genes and the enhancer of the human cytomegalovirus (HCMV) major immediate-early promoter, which contains two such sites. HCMV major immediate-early-chloramphenicol acetyltransferase reporter constructs, transfected into NIH 3T3 fibroblasts, were repressed by Gfi-1, and the repression was abrogated by mutation of critical residues in the two Gfi-1 binding sites. These results suggest that Gfi-1 may play a role in HCMV biology and may contribute to oncogenesis and T-cell activation by repressing the expression of genes that inhibit these processes.
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PMID:Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor. 875

The systemic toxicity of benzothiophene, a sulfur-containing heterocyclic present in petroleum, coal, and their derived products, was studied in male rats following short-term oral exposure. Male Sprague-Dawley rats (130 +/- 20 g) (n = 5 per dose group) were treated with benzothiophene by gavage at dosages of 0, 2, 20 or 200 mg/kg/d for 21 d. In another study, male rats were treated with 0, 100, or 500 ppm benzothiophene via the diet for 28 d. In the gavage study, the 200 mg/kg/d rats showed depressed weight gain, increased relative liver and kidney weights, decreased relative thymus weights, and elevated levels of serum gamma-glutamyltransferase (gamma-GT), hepatic aniline hydroxylase (AH), aminopyrine N-demethylase (APDM), pentoxyresorufin O-dealkylase (PROD), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT) activities. A 4.5-fold increase in urine volume on d 14-21 and a transient, 4-fold increase in urinary ascorbic acid on d 1 were also detected. No treatment related changes in urinary N-acetylglucosaminidase (NAGA) activity were observed. Benzothiophene residues were not detected in adipose tissue, liver, and serum of rats in the 200 mg/kg rats, but a small quantity was detected in the urine. In the diet study, animals fed the 500 ppm diet had increased absolute and relative liver weights, elevated AH, APDM, and GST activities, decreased red blood cell count, and minor increases in serum urea nitrogen and glucose. In summary, benzothiophene produced adverse effects in male rats that included increased relative liver and kidney weights and increased urine output. Benzothiophene also caused increases in hepatic drug metabolizing enzyme activities of a phenobarbital type and a transient elevation in urinary ascorbic acid.
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PMID:Effects of benzothiophene on male rats following short-term oral exposure. 901 32

The tumor promotion potential of 2,3',4,4',5-pentachlorobiphenyl (PCB-118) was studied in a two-stage initiation/promotion bioassay in female Sprague-Dawley rats. The animals were initiated by intraperitoneal administration of N-nitrosodiethylamine after partial hepatectomy. After 5 weeks of recovery, the promotion period commenced by once-weekly subcutaneous administrations of PCB-118 at six dose levels (10, 40, 160, 640, 2500, and 10,000 microg/kg body weight/week) for 20 weeks. In addition, three of these dose levels (40, 640, and 10,000 microg/kg body weight/week) were administered for 52 weeks. Evaluation of hepatic foci positive for glutathione S-transferase P demonstrated that the mono-ortho chlorine substituted congener PCB-118 significantly increased the number of foci/cm3 of liver in the two highest dose groups after 20 weeks, but did not significantly increase the percentage of the liver occupied by foci. After 52 weeks of treatment, both the percentage and the number of foci/cm3 were significantly increased in the highest dose group. A toxic equivalency factor based on foci development during 20 weeks of treatment would be less than 0.00002. Altered relative liver and thymus weights were observed after treatment with both substances as well as an induction of methyl cholanthrene- and phenobarbital-inducible isoenzymes of cytochrome P450 monooxygenase. These results show that PCB-118 has a potency to enhance foci growth in rat liver, although the potency is low compared to that of structurally related compounds.
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PMID:Promotion of altered hepatic foci by 2,3',4,4',5-pentachlorobiphenyl in Sprague-Dawley female rats. 902 79

5-Lipoxygenase activating protein (FLAP), leukotriene-C4 (LTC4) synthase, and microsomal glutathione S-transferase II (microsomal GST-II) are all members of a common gene family that may also include microsomal GST-I. The present work describes the identification and characterization of a novel member of this family termed microsomal glutathione S-transferase III (microsomal GST-III). The open reading frame encodes a 16.5-kDa protein with a calculated pI of 10.2. Microsomal GST-III has 36, 27, 22, and 20% amino acid identity to microsomal GST-II, LTC4 synthase, microsomal GST-I, and FLAP, respectively. Microsomal GST-III also has a similar hydrophobicity pattern to FLAP, LTC4 synthase, and microsomal GST-I. Fluorescent in situ hybridization mapped microsomal GST-III to chromosomal localization 1q23. Like microsomal GST-II, microsomal GST-III has a wide tissue distribution (at the mRNA level) and is predominantly expressed in human heart, skeletal muscle, and adrenal cortex, and it is also found in brain, placenta, liver, and kidney tissues. Expression of microsomal GST-III mRNA was also detected in several glandular tissues such as pancreas, thyroid, testis, and ovary. In contrast, microsomal GST-III mRNA expression was very low (if any) in lung, thymus, and peripheral blood leukocytes. Microsomal GST-III protein was expressed in a baculovirus insect cell system, and microsomes from Sf9 cells containing either microsomal GST-II or microsomal GST-III were both found to possess glutathione-dependent peroxidase activity as shown by their ability to reduce 5-HPETE to 5-HETE in the presence of reduced glutathione. The apparent Km of 5-HPETE was determined to be approximately 7 microM for microsomal GST-II and 21 microM for microsomal GST-III. Microsomal GST-III was also found to catalyze the production of LTC4 from LTA4 and reduced glutathione. Based on these catalytic activities it is proposed that this novel membrane protein is a member of the microsomal glutathione S-transferase super family, which also includes microsomal GST-I, LTC4 synthase, FLAP, and microsomal GST-II.
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PMID:Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activities. 927 57

Chlamydia trachomatis is an obligate intracellular pathogen, long recognized as an agent of blinding eye disease and more recently as a common sexually transmitted infection. Recently, two eukaryotic histone H1-like proteins, designated Hc1 and Hc2, have been identified in Chlamydia. Expression of Hc1 in recombinant Escherichia coli produces chromatin condensation similar to nucleoid condensation observed late in the parasite's own life cycle. In contrast, chromatin decondensation, observed during the early life cycle, accompanies down-regulation and nondetection of Hc1 and Hc2 among internalized organisms. We reasoned that the early upstream open reading frame (EUO) gene product might play a role in Hc1 degradation and nucleoid decondensation since it is expressed very early in the chlamydial life cycle. To explore this possibility, we fused the EUO coding region between amino acids 4 and 177 from C. trachomatis serovar Lz with glutathione S-transferase (GST) and examined the effects of fusion protein on Hc1 in vitro. The purified fusion protein was able to digest Hc1 completely within 1 h at 37 degrees C. However, GST alone exhibited no Hc1-specific proteolytic activity. The chlamydial EUO-GST gene product also cleaves very-lysine-rich calf thymus histone H1 and chicken erythrocyte histone H5 but displays no measurable activity towards core histones H2A, H2B, H3, and H4 or chlamydial RNA polymerase alpha-subunit. This proteolytic activity appears sensitive to the serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride (AEBSF) and aspartic protease inhibitor pepstatin but resistant to high temperature and other broad-spectrum protease inhibitors. The proteolytic activity specified by the EUO-GST fusion product selectively digested the C-terminal portion of chlamydial Hc1, the domain involved in DNA binding, while leaving the N terminus intact. At a molar equivalent ratio of 1:1 between Hc1 and DNA, the EUO gene product cleaves Hc1 complexed to DNA and this cleavage appears sufficient to initiate dissociation of DNA-Hc1 complexes. However, at a higher molar equivalent ratio of Hc1/DNA (10:1), there is partial protection conferred upon Hc1 to an extent that prevents dissociation of DNA-Hc1 complexes.
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PMID:The chlamydial EUO gene encodes a histone H1-specific protease. 929 54

Multiple physiological actions of the hormonal form of vitamin D3, 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), are mediated by a genomic pathway which is initiated by the highly specific recognition and binding by its cognate receptor (vitamin D receptor, VDR) in the target cells. Thus, knowledge of the three-dimensional geometries of the ligand, i.e., 1,25(OH)2D3, and the 1,25(OH)2D3-binding domain of VDR is crucial for a better understanding of diverse physiological roles of this hormone. Recently our laboratory has developed 1 alpha,25-dihydroxyvitamin D3-3 beta-bromoacetate (1,25(OH)2 D3-3-BE) as an affinity labeling reagent for covalently modifying the hormone binding domain of native VDRs from calf thymus and rat osteosarcoma cells and baculovirus-expressed recombinant human VDR (hVDR). In the present report, we report affinity labeling of the hormone binding domain of hVDR, expressed in Escherichia coli as a glutathione S-transferase fusion partner, site-specific cleavage of the affinity-labeled VDR with 3-bromo-3-methyl-2-(2-nitrophenylmercapto)- 3H-indole, and identification of the C-terminal subdomain of human VDR containing the putative hormone binding site.
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PMID:Identification of the subdomain in the nuclear receptor for the hormonal form of vitamin D3, 1 alpha,25-dihydroxyvitamin D3, vitamin D receptor, that is covalently modified by an affinity labeling reagent. 939 Jan 78


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