Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Destruction of tumor cells is a key function of lymphocytes, but the molecular processes driving it are unclear. Analysis of signal molecules indicated that mitogen-activated protein kinase (MAPK)/extracellular regulated kinase 2 critically controlled lytic function in human NK cells. We now have evidence to indicate that target ligation triggers a Ras-independent MAPK pathway that is required for lysis of the ligated tumor cell. Target engagement caused NK cells to rapidly activate MAPK within 5 min, and PD098059 effectively blocked both MAPK activation and tumoricidal function in NK cells. Target engagement also rapidly activated Ras, detected as active Ras-GTP bound to GST-Raf-RBD, a GST fusion protein linked to the Raf protein fragment containing the Ras-GTP binding domain. However, Ras inactivation by pharmacological disruption with the farnesyl transferase inhibitor, FTI-277, had no adverse effect on the ability of NK cells to lyse tumor cells or to express MAPK activation upon target conjugation. Notably, MAPK inactivation with PD098059, but not Ras inactivation with FTI-277, could interfere with perforin and granzyme B polarization within NK cells toward the contacted target cell. Using vaccinia delivery of N17 Ras into NK cells, we demonstrated that IL-2 activated a Ras-dependent MAPK pathway, while target ligation used a Ras-independent MAPK pathway to trigger lysis in NK cells.
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PMID:Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway. 1103 87

Catalytic promiscuity is a widespread, but poorly understood, phenomenon among enzymes with particular relevance to the evolution of new functions, drug metabolism, and in vitro biocatalyst engineering. However, there is at present no way to quantitatively measure or compare this important parameter of enzyme function. Here we define a quantitative index of promiscuity (I) that can be calculated from the catalytic efficiencies of an enzyme toward a defined set of substrates. A weighted promiscuity index (J) that accounts for patterns of similarity and dissimilarity among the substrates in the set is also defined. Promiscuity indices were calculated for three different enzyme classes: eight serine and cysteine proteases, two glutathione S-transferase (GST) isoforms, and three cytochrome P450 (CYP) isoforms. The proteases ranged from completely specific (granzyme B, J = 0.00) to highly promiscuous (cruzain, J = 0.83). The four drug-metabolizing enzymes studied (GST A1-1 and the CYP isoforms) were highly promiscuous, with J values between 0.72 and 0.92; GST A4-4, involved in the clearance of lipid peroxidation products, is moderately promiscuous (J = 0.37). Promiscuity indices also allowed for studies of correlation between substrate promiscuity and an enzyme's activity toward its most-favored substrate, for each of the three enzyme classes.
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PMID:A quantitative index of substrate promiscuity. 1808 10

The apicomplexan protozoon Eimeria coecicola is an infectious agent of intestinal coccidiosis in rabbits, causing severe injuries in the appendix as the final target, but also in the liver though not being a target. Here, we investigated the effect of E. coecicola on the spleen of the rabbit Oryctolagus cuniculus with respect to structure and gene expression using 2-color Agilent whole rabbit genome oligo-microarray technology in combination with quantitative PCR. At maximal fecal output of E. coecicola oocyts on day 7p.i., the spleen did not contain any parasites, but displayed moderate inflammatory changes evidenced as fused white pulp areas, diffuse appearance of the marginal zones, and increased number of macrophages in the red pulp, eventually resulting in an increased histological score. The infections induced 36 genes to be up-regulated and 156 genes to be down-regulated, among which were 139 genes encoding diverse regions of antibodies. The highest upregulated genes were those encoding granzyme H (10-fold), lim1 (10-fold), xanthine dehydrogenase (9-fold), whereas the downregulated genes could be majorly assigned to the immune response, as e.g. the genes encoding the macrophage cationic peptide-2 (5-fold). Quantitative PCR of genes encoding GZMH, XDH, HSD17B1, SULT3A1, SAA, BPI, MCP-2, and GST exhibited the same transcriptional level as that detected by microarray analysis. The E. coecicola-induced changes in gene expression of the spleen were totally different to those found previously in appendix and liver. Only the granzyme H gene became upregulated in all three organs. Our data indicate that the spleen, though not a final target of E. coecicola, responds to E. coecicola infections, suggesting that the spleen may be part of an orchestrated host defense against E. coecicola critically involving GZMH-expressing NK-cells.
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PMID:Eimeria coecicola: spleen response of Oryctolagus cuniculus. 2320 58

Granzyme B and perforin, two major effector molecules in the granule-mediated cytolytic pathway, are thought to be involved in suppression of tumor progression. In this study, the pGEX-4T-1 expression vector was used to express full-length human perforin or granzyme B as a GST-tagged fusion protein in Escherichia coli (E. coli). GST-tagged proteins were induced with IPTG and purified by GSTrap 4B columns. Purified fusion proteins migrated at the predicted molecular mass on SDS-PAGE and were recognized by specific antibodies. Moreover, the fusion proteins can induce apoptosis and directly inhibit the growth of human laryngeal cancer Hep-2 cells in vitro. These results suggest that active perforin and granzyme B fusion proteins can be produced in E. coli and exhibit anticancer potential in laryngeal cancer cells.
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PMID:Expression, purification and anticancer analysis of GST-tagged human perforin and granzyme B proteins in human laryngeal cancer Hep-2 cells. 2429 45