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)

In searching the expressed sequence tag (EST) data-base of GenBank with coding sequences of 11 known human glutathione S-transferases in conjunction with bioinformatic analysis, we have identified five ESTs that encode a new human glutathione S-transferase (GST) designated GST A4. The cDNA clone (I.M.A.G.E. Consortium cDNA Clone ID 515157) had an insert length of 1279 bp and contains an open reading frame of 666 bp, which encodes a protein of 222 amino acid residues. The GST A4 protein is identical in length to human GST A1 and A2 and is 54% identical to human GST A1 and A2. Sequence comparison with other human GSTs suggests that it is a new GST belonging to the alpha class GSTs. Northern blot analysis and EST database searches have demonstrated that the GST A4 mRNA is expressed at a high level in brain, placenta, and skeletal muscle and much lower in lung and liver. Analysis of the sequence tagged site (STS) database indicated that the GST A4 gene is located on chromosome 6. This STS represents a previously unidentified transcript further confirming the novelty of the new sequence.
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PMID:Identification of a novel human glutathione S-transferase using bioinformatics. 958 21

We have developed a rapid visual method for identifying novel members of gene families. Starting with an evolutionary tree, 20-50 protein query sequences for a gene family are selected from different branches of the tree. These query sequences are used to search the GenBank and expressed sequence tag (EST) DNA databases and their nightly updates using the tfastx3 or tfasty3 programs. The results of all 20-50 searches are collated and resorted to highlight EST or genomic sequences that share significant similarity with the query sequences. The statistical significance of each DNA/protein alignment is plotted, highlighting the portion of the query sequence that is present in the database sequence and the percent identity in the aligned region. The collated results for database sequences are linked using the WWW to the underlying scores and alignments; these links can also be used to perform additional searches to characterize the novel sequence further. With traditional "deep" scoring matrices (BLOSUM50) one can search for previously unrecognized families of large protein superfamilies. Alternatively, by using query sequences and EST libraries from the same species (e. g., human or mouse) together with "shallow" scoring matrices and filters that remove high-identity sequences, one can highlight new paralogs of previously described subfamilies. Using query sequences from the glutathione transferase superfamily, we identified two novel mammalian glutathione transferase families that were recognized previously only in plants. Using query sequences from known mammalian glutathione transferase subfamilies, we identified new candidate paralogs from the mouse class-mu, class-pi, and class-theta families.
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PMID:Panning for genes--A visual strategy for identifying novel gene orthologs and paralogs. 1020 59

A small expressed sequence tag (EST) project generating 506 ESTs from 375 cDNAs was undertaken on the antennae of male Manduca sexta moths in an effort to discover olfactory receptor proteins. We encountered several clones that encode apparent transmembrane proteins; however, none is a clear candidate for an olfactory receptor. Instead we found a greater diversity of odourant binding proteins (OBPs) than previously known in moth antennae, raising the number known for M. sexta from three to seven. Together with evidence of seventeen members of the family from the Drosophila melanogaster genome project, our results suggest that insects may have many tens of OBPs expressed in subsets of the chemosensory sensilla on their antennae. These results support a model for insect olfaction in which OBPs selectively transport and present odourants to transmembrane olfactory receptors. We also found five members of a family of shorter proteins, named sensory appendage proteins (SAPs), that might also be involved in odourant transport. This small EST project also revealed several candidate odourant degrading enzymes including three P450 cytochromes, a glutathione S-transferase and a uridine diphosphate (UDP) glucosyltransferase. Several first insect homologues of proteins known from vertebrates, the nematode Caenorhabditis elegans, yeast and bacteria were encountered, and most have now also been detected by the large D. melanogaster EST project. Only thriteen entirely novel proteins were encountered, some of which are likely to be cuticle proteins.
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PMID:Diversity of odourant binding proteins revealed by an expressed sequence tag project on male Manduca sexta moth antennae. 1062 45

Analysis of the expressed sequence tag (EST) database by sequence alignment allows a rapid screen for polymorphisms in proteins of physiological interest. The human zeta class glutathione transferase GSTZ1 has recently been characterized and analysis of expressed sequence tag clones suggested that this gene may be polymorphic. This report identifies three GSTZ1 alleles resulting from A to G transitions at nucleotides 94 and 124 of the coding region, GSTZ1*A-A94A124; GSTZ1*B-A94G124; GSTZ1*C-G94G124. Polymerase chain reaction/restriction fragment length polymorphism analysis of a control Caucasian population (n = 141) showed that all three alleles were present, with frequencies of 0.09, 0.28 and 0.63 for Z1*A, Z1*B and Z1*C, respectively. These nucleotide substitutions are non-synonymous, with A to G at positions 94 and 124 encoding Lys32 to Glu and Arg42 to Gly substitutions, respectively. The variant proteins were expressed in Escherichia coli as 6X His-tagged proteins and purified by Ni-agarose column chromatography. Examination of the activities of recombinant proteins revealed that GSTZ1a-1a displayed differences in activity towards several substrates compared with GSTZ1b-1b and GSTZ1c-1c, including 3.6-fold higher activity towards dichloroacetate. This report demonstrates the discovery of a functional polymorphism by analysis of the EST database.
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PMID:Discovery of a functional polymorphism in human glutathione transferase zeta by expressed sequence tag database analysis. 1073 72

The global genome research effort has resulted in the creation of extensive DNA and protein sequence databases that are a valuable resource for the identification of new genes and polymorphic variants of enzymes of pharmacogenetic interest. Previously undescribed members of gene families with novel functions and substrate specificities can be identified by database searching and sequence alignment strategies. Since the expressed sequence tag (EST) database contains sequences from many individuals, it can be searched for evidence of polymorphisms that can significantly influence enzyme function. The different approaches to these forms of analysis are reviewed and illustrated with examples from the glutathione transferase gene family.
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PMID:Database analysis and gene discovery in pharmacogenetics. 1109 41

The human expressed sequence tag (EST) database can be searched by different sequence alignment strategies to identify new members of gene families and allelic variants. To illustrate the value of database analysis for gene discovery, we have focused on the glutathione S-transferase (GST) super family, an approach that has led to the identification of the Zeta class. The Zeta class GSTs catalyze the glutathione-dependent biotransformation of alpha-haloacids and the isomerization of maleylacetoacetic acid to fumarylacetoacetic acid, an essential step in the catabolism of tyrosine. Allelic variants of the GST Z1 and GST A2 genes have also been identified by EST database analysis. One GST Z1 variant (GST Z1A) has significantly higher activity with dichloroacetic acid as a substrate than other GST Z1 isoforms. This variant may be important in the clinical treatment of lactic acidosis where dichloroacetic acid is prescribed. Our experience with the application of EST database searching methods suggests that it may be productively applied to other gene families of pharmacogenetic interest.
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PMID:Identification of novel glutathione transferases and polymorphic variants by expressed sequence tag database analysis. 1125 48

Total RNA differential display (DD) using random primers was performed for rat orthotopic liver transplantation (OLT) models. DA (RT1a) donor livers were transplanted into DA, PVG (RT1c), and LEW (RT1l) recipients: (1) syngeneic OLT (DA-DA): no rejection occurs; (2) allogeneic OLT (DA-PVG): rejection occurs, but is naturally overcome without immunosuppression; (3) allogeneic OLT (DA-LEW): animals die of acute rejection within 14 days. cDNA was isolated from selected bands, re-amplified for sequencing, and confirmed by Northern blots. Two down-regulated genes were observed in day-7 allogeneic OLT livers (DA-PVG, DA-LEW), while they were consistently expressed in day-7 syngeneic OLT (DA-DA) livers. These two genes were identified as alpha-glutathione sulfotransferase (alpha-GST) Ya gene and estrogen sulfotransferase (EST), respectively. Northern blots confirmed that their expression was down-regulated in OLT (DA-PVG) livers on days 7-26 and gradually restored. The mRNA expression of GST and EST may be good markers to predict rejection or induction of tolerance.
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PMID:Identification of two down-regulated genes in rat liver allografts by mRNA differential display. 1149 4

The class Kappa family of glutathione S-transferases (GSTs) currently comprises a single rat subunit (rGSTK1), originally isolated from the matrix of liver mitochondria [Harris, Meyer, Coles and Ketterer (1991) Biochem. J. 278, 137-141; Pemble, Wardle and Taylor (1996) Biochem. J. 319, 749-754]. In the present study, an expressed sequence tag (EST) clone has been identified which encodes a mouse class Kappa GST (designated mGSTK1). The EST clone contains an open reading frame of 678 bp, encoding a protein composed of 226 amino acid residues with 86% sequence identity with the rGSTK1 polypeptide. The mGSTK1 and rGSTK1 proteins have been heterologously expressed in Escherichia coli and purified by affinity chromatography. Both mouse and rat transferases were found to exhibit GSH-conjugating and GSH-peroxidase activities towards model substrates. Analysis of expression levels in a range of mouse and rat tissues revealed that the mRNA encoding these enzymes is expressed predominantly in heart, kidney, liver and skeletal muscle. Although other soluble GST isoenzymes are believed to reside primarily within the cytosol, subcellular fractionation of mouse liver demonstrates that this novel murine class Kappa GST is associated with mitochondrial fractions. Through the use of bioinformatics, the genes encoding the mouse and rat class Kappa GSTs have been identified. Both genes comprise eight exons, the protein coding region of which spans approx. 4.3 kb and 4.1 kb of DNA for mGSTK1 and rGSTK1 respectively. This conservation in primary structure, catalytic properties, tissue-specific expression, subcellular localization and gene structure between mouse and rat class Kappa GSTs indicates that they perform similar physiological functions. Furthermore, the association of these enzymes with mitochondrial fractions is consistent with them performing a specific conserved biological role within this organelle.
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PMID:Biochemical and genetic characterization of a murine class Kappa glutathione S-transferase. 1272 May 45

We have identified a cDNA clone encoding BMP receptor-associated molecule 1 (BRAM1) from the zebrafish expressed sequence tag (EST) database. The 2606 bp full-length bram1 cDNA was cloned, and further confirmed by nucleotide sequencing. The zebrafish sequence encodes a protein of 195 amino acids with an evolutionarily conserved MYND domain, which displays approximately approximately 98% homology with human and mouse BRAM1, and approximately approximately 64% homology with C. elegans BRA-1 and BRA-2. The bram1 gene, composed of five exons and four introns, spans approximately approximately 14 kb on linkage group 14 of the zebrafish genome. RT-PCR and whole mount in situ hybridization analyses disclosed that zebrafish BRAM1 is a maternal factor. The protein interacts directly with zebrafish BMP Receptor type IA, as observed from GST-pull down and co-immunoprecipitation assays. Furthermore, cotransfection of zebrafish BRAM1 with the corresponding BMP receptor resulted in down-regulation of BMP-mediated signaling. Our results collectively indicate that BRAM1 plays a biological role during zebrafish development.
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PMID:Molecular cloning, expression and characterization of the zebrafish bram1 gene, a BMP receptor-associated molecule. 1645 8

To establish a monitoring system for gene expression profiles related to chemical contamination in wild common cormorants (Phalacrocorax carbo), the present study constructed an oligo array designed from expressed sequence tag (EST) sequences of the cormorant liver, where 1061 unique oligonucleotides were spotted. Common cormorants were collected from Lake Biwa, Japan in May 2001 and 2002. With the use of this oligo array, gene expression profiles in the liver of individual specimens were evaluated. To determine the expression patterns of genes altered by environmental contaminants, relationships between concentrations of persistent organochlorines including polychlorinated dibenzo-p-dioxins, furans, polychlorinated biphenyls, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), chlordane compounds (CHLs), butyltins, and bisphenol A (BPA) and expression levels of each gene in the cormorant liver were examined using stepwise multiple regression analysis. The reliability of data obtained by the oligo array was further confirmed by quantifying the expression levels of certain genes using real-time RT-PCR. The 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalent (TEQ) level was positively correlated with both cytochrome P4501A4 and 1A5 gene expression. In addition, the mRNA level of an antioxidant enzyme, Cu/Zn superoxide dismutase, was negatively correlated with hepatic total TEQ. Other antioxidant enzymes, glutathione peroxidase 3 and glutathione S-transferase class mu, were negatively correlated with HCHs and BPA levels, respectively. The mRNA expression level of a nonenzymatic antioxidant, haptoglobin, was negatively but not significantly correlated with CHLs. These results led to a hypothesis that wild cormorant population may suffer from oxidative stress due to chemically induced formation of reactive oxygen species and subsequent reduction of antioxidant resistance. Thus, the cormorant oligo array may be a useful monitoring tool to identify specific gene expression profiles altered by various environmental contaminants. Although further research is required to clarify a definitive cause-and-effect relationship, the current study provides valuable information on contaminant-responsive genes to predict potential effects on wildlife in a real environment.
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PMID:Gene expression profiling in common cormorant liver with an oligo array: assessing the potential toxic effects of environmental contaminants. 1650 60


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