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:3.2.1.31 (beta-glucuronidase)
7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The actions of the novel metabolically stable and selective prostaglandin D2 receptor agonist ZK 118.182 ((5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-15- hydroxy-16,17,18,19,20-pentanor-3-oxa-5,13-prostadienoic acid) were studied in human platelets and polymorphonuclear neutrophils in vitro and compared to the naturally occurring agonist prostaglandin D2. ZK 118.182 inhibited collagen and ADP induced platelet aggregation more potently than prostaglandin D2 (IC50: 15 nM versus 60 nM) but was less effective than the stable prostacyclin mimetic iloprost (IC50: 3 nM). The same rank order of potencies was observed for the inhibition of collagen-induced platelet ATP secretion. A dose-dependent activation of adenylate cyclase could be demonstrated by ZK 118.182 which was comparable to that of prostaglandin D2 with respect to the concentration needed for half maximal stimulation (ED50) maximal cAMP level achievable. ZK 118.182 also dose dependently reduced the formyl-methionyl-leucyl-phenylalanine (FMLP) or platelet-activating factor (PAF) induced activation of polymorphonuclear neutrophils. Both, the oxygen burst resulting in the generation of superoxide anions and the degranulation of polymorphonuclear neutrophils accompanied by release of the lysosomal enzyme beta-glucuronidase, were significantly and dose dependently inhibited. ZK 118.182 was more potent than prostaglandin D2 in inhibiting polymorphonuclear neutrophil activation in all tests performed. In summary, ZK 118.182 is a prostaglandin D2 mimetic exerting potent inhibitory effects on human platelets and polymorphonuclear neutrophils.
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PMID:Inhibition of human platelets and polymorphonuclear neutrophils by the potent and metabolically stable prostaglandin D2 analog ZK 118.182. 752 76

Alanine and phenylalanine tRNA sequences were amplified by PCR from Arabidopsis thaliana nuclear DNA using degenerate oligonucleotides which introduced specific mutations into the acceptor stem. The aminoacylation of T7 RNA polymerase transcripts of these sequences was investigated in vitro using partially purified bean alanyl- or phenylalanyl-tRNA synthetase. In parallel, the in vivo activity of amber suppressor derivatives of these tRNAs was investigated in transient expression assays in tobacco protoplasts using a beta-glucuronidase (GUS) reporter gene containing a premature amber stop codon. The results show that mutation of the G3:U70 base pair to G3:C70 blocks aminoacylation of plant alanine tRNA, whilst conversion of the G3:C70 pair normally found in plant tRNA(Phe) to G3:U70 enables the mutated tRNA(Phe) to be a good substrate for alanyl-tRNA synthetase and impairs its aminoacylation with phenylalanine. In addition, the amber suppressor derivative of wild-type tRNA(Phe) showed very little suppressor activity in vivo, and was poorly aminoacylated with phenylalanine in vitro, suggesting that the anticodon is a major identity determinant for tRNA(Phe) in plant cells.
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PMID:Characterization of some major identity elements in plant alanine and phenylalanine transfer RNAs. 753 29

We studied the effects of polymorphonuclear leukocytes (PMNLs) activated by N-formyl-methionyl-leucyl-phenylalanine on the endothelium-dependent relaxation of the rabbit basilar artery (BA). In the presence of activated PMNLs the maximal vessel relaxation to acetylcholine (ACh) and bradykinin (endothelium-dependent dilators) was decreased from 62 +/- 7 and 48 +/- 6% to 23 +/- 9 and 19 +/- 7, respectively, (p < 0.05). The endothelium-independent relaxation to nitroprusside was not affected by PMNLs. When PMNLs were activated in the organ chamber in the presence of a low concentration of platelet-activating factor (PAF, 10(-10) mol/l), the depression of ACh- and bradykinin-induced relaxation increased by 27 +/- 9 and 23 +/- 7%, respectively (p < 0.05), though at this concentration PAF alone did not cause PMNLs to induce endothelial dysfunction. In addition, in the presence of PAF, activated PMNLs inhibited endothelium-dependent relaxation at lower cell concentrations and shorter periods of contact with the endothelium. PMNL effects on the endothelium were correlated with the level of cell exocytosis as tested by accumulation of beta-glucuronidase activity. In the presence of PAF, accumulation of this activity increased from 46 +/- 6 to 79 +/- 8 U/ml (p < 0.05). Examination of BA segments by scanning electron microscopy revealed that, after the treatment with activated PMNLs, the endothelium was morphologically preserved, but in the presence of PAF PMNLs caused more apparent microlesions in the endothelial layer. We conclude that small quantities of PAF potentiate the activation of marginated PMNLs. These cells then become more aggressive towards the endothelium, producing significant depression of the endothelium-dependent relaxation.
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PMID:Leukocyte-induced endothelial dysfunction in the rabbit basilar artery: modulation by platelet-activating factor. 755 83

We have investigated the interaction between quartz and granulocytes with respect to complement receptor expression. When N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated leukocytes were exposed to quartz at 37 degrees C, CR1 was down-regulated but CR3 was not affected. This was a direct effect on granulocytes because it occurred in a similar fashion when mixed leukocyte suspensions and isolated granulocyte populations were used as targets for quartz. The observed down-regulation by quartz was not affected by the microfilament-disrupting agent cytochalasin B and the total detectable pool of CR1 was reduced after quartz exposure. When protease inhibitors, such as aprotinin or phenylmethanesulfonyl fluoride, were present during quartz exposure, the down-regulation of CR1 was less pronounced, but this was not the case not when protease inhibitors such as EDTA-Na2 and pepstatin were present. Exposure to quartz was not accompanied by a pronounced release of beta-glucuronidase (marker for the primary granules) or vitamin B12 binding protein (marker for the secondary granules). In contrast to quartz, exposure to alumina did not affect the expression of CR1 and CR3. The spontaneous mobilization of CR1 at 37 degrees C was reduced when quartz was present but the CR3 mobilization was unaffected. Our results indicate that quartz induces a granule protease-dependent selective shedding of CR1 but not CR3 despite a low degree of degranulation.
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PMID:Quartz selectively down-regulates CR1 on activated human granulocytes. 767 48

Two commercially available media recommended for the isolation and rapid identification of Escherichia coli from urinary tract infections were supplemented with L-phenylalanine and L-tryptophan. The non-selective medium proved suitable for the direct detection of lactose fermentation, beta-glucuronidase and phenylalanine deaminase activities, indole production and the oxidase test. It was highly efficient in making a presumptive identification at species level of the most common gram-negative urinary pathogens, E. coli, Proteus mirabilis and Pseudomonas aeruginosa, that account for c. 85% of all urinary isolates. Among the gram-positive isolates, most colonies were non-fluorescent and could be separated into staphylococci and enterococci on the basis of the catalase test. Fluorescent colonies were found to be Staphylococcus haemolyticus isolates, 61% of which were fluorescent. The selective medium proved suitable for the same biochemical tests, with the exception of indole, which was not visible against the red colour of the medium. Therefore, the differentiation of P. mirabilis from other Proteus-Providencia species was impossible on this medium.
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PMID:Rapid identification of micro-organisms from urinary tract infections by beta-glucuronidase, phenylalanine deaminase, cytochrome oxidase and indole tests on isolation media. 796 14

The mode of action of the new leukotriene synthesis inhibitor BAY X1005 ((R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid) and structurally-related quinoline derivatives is reflected by the binding to a high-affinity binding site presumably identical to FLAP (five lipoxygenase activating protein). In addition to FLAP, we have identified a second BAY X1005 (low-affinity) binding site localized in the granule fraction of human PMNL (polymorphonuclear leukocytes). Based on the hypothesis that the corresponding target protein might be involved in the regulation of granule release, the influence of the leukotriene synthesis inhibitors BAY X1005 and MK-886 and the direct 5-LOX (5-lipoxygenase, EC 1.13.11.34) inhibitor A-64077 on the A23187- and fMLP (N-formyl-methionyl-leucyl-phenylalanine)-stimulated release of beta-glucuronidase (as a marker for azurophil granules) and vitamin B12-binding protein (as a marker for specific granules) was investigated. In contrast to MK-886, neither BAY X1005 nor A-64077 significantly affected fMLP-stimulated granule release. This was also true for the A23187-stimulated release of specific granules; however, under the same conditions the A23187-stimulated release of azurophil granules was almost totally inhibited by all three compounds. No obvious relationship between the corresponding IC50 values and the ability of these compounds to compete for BAY X1005 binding at the low-affinity binding site existed. Instead, by extending these studies to additional inhibitors, a correlation between the IC50 values for inhibition of A23187-stimulated (i) beta-glucuronidase release and (ii) LTB4 (leukotriene B4) synthesis was found (r = 0.969, N = 7). This relationship was independent of the mode of action of the compounds, namely direct 5-LOX inhibition or indirect 5-LOX inhibition mediated via binding to FLAP. These results suggest that 5-LOX metabolites may be involved in A23187-stimulated azurophil granule release. Of the two main biologically active 5-LOX metabolites synthesized under these conditions (LTB4 and 5-hydroxyeicosatetraenoic acid), only LTB4 stimulated beta-glucuronidase release to nearly the same extent as A23187. In addition, this metabolite significantly enhanced A23187-stimulated beta-glucuronidase release, but only at A23187 concentrations (> or = 0.25 mumol/L) which by themselves were not sufficient to trigger LTB4 formation. Moreover, the inhibition of A23187-stimulated beta-glucuronidase release by BAY X1005 or A-64077 was totally reversed by the addition of LTB4.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ca2+ ionophore A23187-stimulated secretion of azurophil granules in human polymorphonuclear leukocytes is largely mediated by endogenously formed leukotriene B4. 804 28

Two beta-glucuronidase-deficient Mennonite siblings were found to be homozygous for a mutation in exon 3 of the beta-glucuronidase gene that produces a Leu-->Phe substitution (L176F). The siblings also have the previously described benign polymorphism, P649L. Although their cultured fibroblasts contained 1.5-2.2% of normal beta-glucuronidase activity, transient expression of the L176F/P649L cDNA in COS cells produced nearly as much enzyme activity as the wild-type control cDNA. The L176F/P649L enzyme was as stable as wild-type enzyme following endocytosis by fibroblasts and delivery to lysosomes, but was more labile to heat inactivation at 65 degrees C. To study the mutant enzyme at lower levels of expression, we stably transfected mouse mucopolysaccharidosis type VII cells with the L176F/P649L cDNA and selected single-copy cell lines. Metabolic labeling with [35S]methionine revealed that cell lines expressing the mutant enzyme activity at low levels (7-10% of the wild type) actually produced the same amount of enzyme protein as the cell lines expressing the more active wild-type enzyme. However, the cell lines expressing four times this much mutant enzyme protein produced 150-200% as much enzyme activity as the cell line expressing the single-copy wild-type cDNA. These data suggest that overexpression can drive the folding reaction or the self-association of mutant monomers to form active tetramers and, at least partially, correct the beta-glucuronidase deficiency seen at low levels of expression with certain missense mutations.
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PMID:Overexpression rescues the mutant phenotype of L176F mutation causing beta-glucuronidase deficiency mucopolysaccharidosis in two Mennonite siblings. 808 38

Human neutrophils were activated by the bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) to produce superoxide (O2-) and to release the primary granule enzyme beta-glucuronidase and the predominantly secondary granule enzyme lysozyme. Pretreatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) increased the secretion of all three substances upon addition of fMLP. The augmentation by GM-CSF was significantly attenuated by the 5-lipoxygenase inhibitor AA861 and by the guanylate cyclase inhibitor LY83583. The secretion induced by fMLP alone was much less affected by either of the two inhibitors. AA861 inhibited leukotriene B4 production in neutrophils primed with GM-CSF and stimulated with fMLP, and LY83583 inhibited GM-CSF-evoked increases of 3',5'-guanosine monophosphate. The data suggest that activation of lipoxygenase and guanylate cyclase is not critical to the fMLP stimulation pathway, but they may be important components of the pathway by which GM-CSF augments neutrophil responses to fMLP. However, AA861 and LY83583 may have important actions in addition to inhibition of 5-lipoxygenase and guanylate cyclase.
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PMID:Effects of inhibition of lipoxygenase and guanylate cyclase on human neutrophil responses to formyl peptide and granulocyte-macrophage colony-stimulating factor. 810 55

Polychlorinated biphenyls (PCBs) are known to be immunotoxic, yet the effects on neutrophil (PMN) function are not well characterized. We incubated PMNs isolated from rat peritoneum with a mixture of PCB congeners, Aroclor 1242, in the absence or presence of either phorbol myristate acetate (PMA) to stimulate generation of superoxide anion (O2-) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) to induce degranulation (measured as release of beta-glucuronidase). Aroclor 1242 alone stimulated O2- production at a concentration of 10 micrograms/ml. Significant cytotoxicity was not observed under these conditions. This concentration of Aroclor 1242 also increased O2- generation in PMNs activated with 20 ng PMA/ml. In the presence of a concentration of PMA (2 ng/ml) that by itself did not stimulate production of O2-, 1 microgram Aroclor 1242/ml caused significant generation of O2-, indicating synergy between Aroclor 1242 and PMA. Aroclor 1242 caused release of beta-glucuronidase from quiescent PMNs; however, in PMNs stimulated with fMLP to undergo degranulation, Aroclor 1242 inhibited release of beta-glucuronidase. The effects of two PCB congeners, one that binds to the Ah receptor (3,3', 4,4'-tetrachlorobiphenyl) and one that has little affinity for this receptor (2,2', 4,4'-tetrachlorobiphenyl) were examined. 3,3', 4,4'-Tetrachlorobiphenyl had no effect on PMN function in vitro, whereas 2,2', 4,4'-tetrachlorobiphenyl had effects similar to those observed with Aroclor 1242. These results indicate that PCBs affect PMN function in vitro in a complex manner, stimulating or inhibiting function under different conditions. These effects are apparently not mediated through the Ah receptor.
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PMID:Neutrophil function after exposure to polychlorinated biphenyls in vitro. 811 54

The effect of glycosaminoglycans (GAGs) such as sulodexide, low molecular mass dermatan sulfate, heparin and some derivatives with different degrees and types of sulfation was studied on cathepsin G- or thrombin-stimulated platelets and n-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated polymorphonuclear leucocytes (PMNs). All GAGs (0.01-20 micrograms/mL) inhibited both platelet aggregation induced by cathepsin G and its catalytic activity. Thrombin-induced platelet aggregation in contrast was only prevented by heparin, sulodexide and dermatan (2-100 micrograms/mL). All GAGs, except 2-O,N-desulfated heparin, inhibited beta-glucuronidase and lysozyme release, as well as beta-glucuronidase activity and PMN superoxide production by the peptide fMLP. The efficacy of GAGs was clearly dependent on the degree and type of sulfation since dermatan and N-desulfated heparins were comparatively less effective. The observation that heparin and other GAGs inhibit platelet activation induced by the PMN protease cathepsin G may help determine whether mechanisms of action other than anticoagulation are critical in the antithrombotic activity of heparin and related compounds.
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PMID:Effects of glycosaminoglycans on platelet and leucocyte function: role of N-sulfation. 837 48


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