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)

The PAC(1), VPAC(1) and VPAC(2) receptors are members of the secretin (Group II) family of G protein-coupled receptors. All members of this family activate adenylate cyclase and several have also been shown to activate phospholipase C. We have recently reported that the rat VPAC(1), VPAC(2) and PAC(1) receptors activate phospholipase D and that distinct pathways are utilised by two intracellular loop 3 splice variants of PAC(1), one of which is ARF-dependent. Phospholipase D activation by the hop1, but not the null (short), form of the PAC(1) receptor is sensitive to brefeldin A, an inhibitor of GTP exchange at ARF. We have expressed the null and hop1 intracellular loop 3 domains of the human PAC(1) receptor in bacteria as GST-fusion proteins and used them as peptide affinity matrices to determine whether a functional interaction exists between these domains and ARF. Using this GST pull-down assay, we have shown binding of the small G protein ARF6 to the hop1 but not the null domain of this receptor.
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PMID:Specific interaction between the hop1 intracellular loop 3 domain of the human PAC(1) receptor and ARF. 1240 33

The thioredoxin-like fold has a betaalphabetaalphabetabetaalpha topology, and most proteins/domains with this fold have a topologically conserved cis -proline residue at the N-terminus of beta-strand 3. This residue plays an important role in the catalytic function and stability of thioredoxin-like proteins, but is reported not to contribute towards the stability of glutathione S-transferases (GSTs) [Allocati, Casalone, Masulli, Caccarelli, Carletti, Parker and Di Ilio (1999) FEBS Lett. 445, 347-350]. In order to further address the role of the cis -proline in the structure, function and stability of GSTs, cis -Pro-56 in human GST (hGST) A1-1 was replaced with a glycine, and the properties of the P56G mutant were compared with those of the wild-type protein. Not only was the catalytic function of the mutant dramatically reduced, so was its conformational stability, as indicated by equilibrium unfolding and unfolding kinetics experiments with urea as denaturant. These findings are discussed in the context of other thioredoxin-like proteins.
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PMID:The role of an evolutionarily conserved cis-proline in the thioredoxin-like domain of human class Alpha glutathione transferase A1-1. 1257 33

Recently, numerous studies have shown antioxidant actions of melatonin. Melatonin at both physiological and pharmacological levels stimulates glutathione peroxidase, glutathione reductase and superoxide dismutase activities in the brains of rats and chickens. This study was designed to evaluate the effect of melatonin on nephropathy and oxidative stress under constant light exposure. Nephropathy was induced by adriamycin administered in a single dose (25 mg kg(-1) b.w., i.p.). Melatonin was injected i.p. (1,000 microg kg(-1) b.w./day). Malondialdehyde, reduced glutathione, glutathione peroxidase, glutathione reductase, glutathione transferase, catalase and superoxide dismutase were determined in kidney. Urea, creatinine and total proteins in plasma and proteinuria were evaluated and melatonin was determined. Results show a decrease in melatonin levels. Similar effects occurred with the antioxidant enzyme activities and reduced glutathione. Likewise, adriamycin and constant light induced significant enhancement of malondialdehyde. All changes induced both by adriamycin and constant light were reverted to normal by melatonin administration. Constant light exposure was associated with an increase in oxidative stress and nephropathy induced by adriamycin. Treatment with melatonin decreased lipid peroxides, and permitted a recovery of reduced glutathione, scavenger enzyme activity and parameters of renal function.
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PMID:Melatonin effect on renal oxidative stress under constant light exposure. 1257 19

We have used GST pulldowns from A431 cell cytosol to identify three new binding partners for the gamma-adaptin appendage: Snx9, ARF GAP1, and a novel ENTH domain-containing protein, epsinR. EpsinR is a highly conserved protein that colocalizes with AP-1 and is enriched in purified clathrin-coated vesicles. However, it does not require AP-1 to get onto membranes and remains membrane-associated in AP-1-deficient cells. Moreover, although epsinR binds AP-1 via its COOH-terminal domain, its NH(2)-terminal ENTH domain can be independently recruited onto membranes, both in vivo and in vitro. Brefeldin A causes epsinR to redistribute into the cytosol, and recruitment of the ENTH domain requires GTPgammaS, indicating that membrane association is ARF dependent. In protein-lipid overlay assays, the epsinR ENTH domain binds to PtdIns(4)P, suggesting a possible mechanism for ARF-dependent recruitment onto TGN membranes. When epsinR is depleted from cells by RNAi, cathepsin D is still correctly processed intracellularly to the mature form. This indicates that although epsinR is likely to be an important component of the AP-1 network, it is not necessary for the sorting of lysosomal enzymes.
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PMID:EpsinR: an ENTH domain-containing protein that interacts with AP-1. 1258 59

The human papillomavirus (HPV) capsid consists of 360 copies of the major capsid protein, L1, arranged as 72 pentamers on a T=7 icosahedral lattice, with substoichiometric amounts of the minor capsid protein, L2. In order to understand the arrangement of L2 within the HPV virion, we have defined and biochemically characterized a domain of L2 that interacts with L1 pentamers. We utilized an in vivo binding assay involving the coexpression of recombinant HPV type 11 (HPV11) L1 and HPV11 glutathione S-transferase (GST) L2 fusion proteins in Escherichia coli. In this system, L1 forms pentamers, GST=L2 associates with these pentamers, and L1+L2 complexes are subsequently isolated by using the GST tag on L2. The stoichiometry of L1:L2 in purified L1+L2 complexes was 5:1, indicating that a single molecule of L2 interacts with an L1 pentamer. Coexpression of HPV11 L1 with deletion mutants of HPV11 L2 defined an L1-binding domain contained within amino acids 396 to 439 near the carboxy terminus of L2. L2 proteins from eight different human and animal papillomavirus serotypes were tested for their ability to interact with HPV11 L1. This analysis targeted a hydrophobic region within the L1-binding domain of L2 as critical for L1 binding. Introduction of negative charges into this hydrophobic region by site-directed mutagenesis disrupted L1 binding. L1-L2 interactions were not significantly disrupted by treatment with high salt concentrations (2 M NaCl), weak detergents, and urea concentrations of up to 2 M, further indicating that L1 binding by this domain is mediated by strong hydrophobic interactions. L1+L2 protein complexes were able to form virus-like particles in vitro at pH 5.2 and also at pH 6.8, a pH that is nonpermissive for assembly of L1 protein alone. Thus, L1/L2 interactions are primarily hydrophobic, encompass a relatively short stretch of amino acids, and have significant effects upon in vitro assembly.
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PMID:Interactions between papillomavirus L1 and L2 capsid proteins. 1266 88

Accidental hypothermia is a common companion of trauma/haemorrhage, and several clinical studies have identified reduced body temperature as an independent risk predisposing to increased morbidity and mortality. Accordingly, the majority of trauma care guidelines prescribe early and aggressive rewarming of hypothermic patients. Enzyme reactions are generally downregulated at temperatures below 37 degrees C, including most of those responsible for the inflammatory response. The rationale for adhering to these recommendations uncritically may therefore be questioned. In a rat model of mild hypothermia and haemorrhagic shock we wanted to compare the influence of rapid rewarming with persistently reduced temperature on the synthesis of early inflammatory mediators and organ function. Thirty-four male albino Sprague-Dawley rats were studied. Withdrawal of 2.5 ml blood/100 g body weight was performed over 10 min, with simultaneous reduction of body temperature to 32.5-33.5 degrees C. Seventy-five minutes after initiation of bleeding, two-thirds of the shed blood was retransfused. One group (n=17) was rewarmed to normothermia, the other (n=17) was kept hypothermic. The study was terminated after an observation period of 2 h. At the end of the study the rewarmed animals had a significantly lower mean arterial pressure, higher heart rate, higher synthesis of reactive oxygen species from peritoneal phagocytes, increased circulating levels of nitric oxide, and higher values of the organ markers aspartate aminotransferase and urea. The pro-inflammatory cytokines TNF-alpha and IL-6, the anti-inflammatory cytokine IL-10, the organ markers alanine aminotransferase, alpha-glutathione S-transferase and creatinine, as well as organ injury scores were equal in both groups. Three rewarmed rats died prematurely, versus one hypothermic animal. In conclusion, the results suggest that during the early stages after haemorrhagic shock, rapid rewarming from mild hypothermia may have unfavourable effects both on basic haemodynamic variables, and on the internal inflammatory environment of cells and tissues.
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PMID:Rapid rewarming after mild hypothermia accentuates the inflammatory response after acute volume controlled haemorrhage in spontaneously breathing rats. 1286 16

The ADP-ribosylation factor 6 (ARF6) small GTPase functions as a GDP/GTP-regulated switch in the pathways that stimulate actin reorganization and membrane ruffling. The formation of active ARF6GTP is stimulated by guanine nucleotide exchange factors (GEFs) such as cytohesins, which translocate to the plasma membrane in agonist-stimulated cells by binding the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate through the pleckstrin homology domain with subsequent ARF6 activation. Using cytohesin 2 as bait in yeast two-hybrid screening, we have isolated a cDNA encoding a protein termed interaction protein for cytohesin exchange factors 1 (IPCEF1). Using yeast two-hybrid and glutathione S-transferase pull-down assays coupled with deletion mutational analysis, the specific domains required for the cytohesin 2-IPCEF1 interaction were mapped to the coiled-coil domain of cytohesin 2 and the C-terminal 121 amino acids of IPCEF1. IPCEF1 also interacts with the other members of the cytohesin family of ARF GEFs, suggesting that the interaction with IPCEF1 is highly conserved among the cytohesin family of ARF GEFs. The interaction of cytohesin 2 and IPCEF1 in mammalian cells was demonstrated by immunoprecipitation. Immunofluorescence analysis revealed that IPCEF1 co-localizes with cytohesin 2 to the cytosol in unstimulated cells and translocates to the plasma membrane via binding to cytohesin 2 in epidermal growth factor-stimulated cells. However, a deletion mutant of IPCEF1 that lacks the cytohesin 2 binding site failed to co-migrate with cytohesin 2 to the membrane in stimulated cells. The functional significance of the IPCEF1-cytohesin 2 interaction is demonstrated by showing that IPCEF1 increases the in vitro and in vivo stimulation of ARFGTP formation by cytohesin 2.
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PMID:Interaction protein for cytohesin exchange factors 1 (IPCEF1) binds cytohesin 2 and modifies its activity. 1292 Jan 29

Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1beta] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1beta. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 microg per mouse) or the DNA-binding A box (600 microg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.
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PMID:Reversing established sepsis with antagonists of endogenous high-mobility group box 1. 1469 89

A cDNA clone encoding a rac-like small GTP binding protein was isolated from a cDNA library of Chinese cabbage (Brassica campestris L. ssp. pekinensis) flower buds and named Brac1. The Brac1 cDNA contains an open reading frame encoding 198 amino acid residues with an estimated molecular mass of 21,690 Da and this coding region has conserved residues and motifs unique to the Rho subfamily of proteins. The deduced amino acid sequence of the Brac1 protein is closely related to that of Arabidopsis thaliana Arac3 (91%), but it shares relatively little homology with other members of the Ras superfamily (about 30% identity). To further characterize Brac1, a pGBrac1 expression vector consisting of PCR-amplified Brac1 cDNA plus glutathione S-transferase (GST) and pBKS(+)II was used to purify the protein. Using a PEI-cellulose/TLC plate, GTPase activity of this protein was confirmed and competition binding studies, using the guanine nucleotides, ATP, UTP and CTP, revealed that the di- and triphosphate forms of guanine nucleotides strongly bind Brac1. Membrane-bound PLD activity was synergistically enhanced by Brac1 in the presence of protein kinase C, but not in the presence of ARF (ADP-ribosylation factor). Genomic analysis indicated that Brac1 belongs to a multigene family. Brac1 transcripts were expressed in all the organs of Brassica, but were especially prevalent in flower buds.
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PMID:A rac-like small G-protein from Brassica campestris activates a PKC-dependent phospholipase D. 1469 72

Dissociation and unfolding of homodimeric glutathione S-transferase Y7F mutant from Schistosoma japonicum (SjGST-Y7F) were investigated at equilibrium using urea as denaturant. The conserved residue Tyr7 plays a central role in the catalytic mechanism and the mutation Tyr-Phe yields an inactive enzyme that is able to bind the substrate GSH with a higher binding constant than the wild type enzyme. Mutant SjGST-Y7F is a dimer at pH 6 or higher and a stable monomer at pH 5 that binds GSH (K value of 1.2x10(5)+/-6.4x10(3)M(-1) at pH 6.5 and 6.3x10(4)+/-1.25x10(3)M(-1) at pH 5). The stability of the SjGST-Y7F mutant was studied by urea induced unfolding techniques (DeltaG(W)=13.86+/-0.63kcalmol(-1) at pH 6.5 and DeltaG(W)=11.22+/-0.25kcalmol(-1) at pH 5) and the monomeric form characterized by means of size exclusion chromatography, fluorescence, and electrophoretic techniques.
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PMID:A monomer form of the glutathione S-transferase Y7F mutant from Schistosoma japonicum at acidic pH. 1471 38


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