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 levels of four acid hydrolases, beta-N-acetyl glucosaminidase, beta-glucuronidase, beta-galactosidase, and acid phosphatase, and the extent of their release (release II) by thrombin was determined in platelets from nine normal subjects, nine patients with storage pool disease, and in normal platelets which had been exposed to aspirin. The levels of all four hydrolases were normal in patients with SPD. However, release of three of these hydrolases (acid phosphatase was an exception) by low concentrations of thrombin (0.015 and 0.04 U/ml) was decreased in the patients as a group, although considerable variation in the extent of release of each enzyme was noted. In contrast, aspirin failed to inhibit release II in normal platelets (except for a slight impairment in the release of beta-N-acetyl glucosaminidase), although release I (serotonin, ATP and ADP) was inhibited. All release defects could be overcome by using higher concentrations of thrombin (0.2 U/ml). The normal levels of acid hydrolases in the platelets of patients with SPD (who are deficient in the platelet dense granules) suggest that these enzymes are not normally stored in the dense granules, but rather in alpha-granules. The findings also support the conclusions of previous studies that the release reaction is impaired in SPD. This release defect appears to be different from that seen in normal platelets after exposure to aspirin.
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PMID:Content and thrombin-induced release of acid hydrolases in gel-filtered platelets from patients with storage pool disease. 113 24

The pluripotent human erythroleukaemia cell line, HEL, possesses erythrocytic, megakaryocytic and macrophage-like properties. With respect to signal transduction, HEL cells have been used as a model system for platelets, but little attention has been paid to their phagocytic properties. We studied the effects of various receptor agonists on the intracellular free Ca2+ concentration ([Ca2+]i) in HEL cells. Thrombin, platelet-activating factor (PAF), ATP, UTP, prostaglandins E1 and E2 (PGE1 and PGE2), the PGE2 analogue sulprostone and the stable PGI2 analogues iloprost and cicaprost increased [Ca2+]i. ADP was less effective than ATP, and UDP was unable to increase [Ca2+]i. The increases in [Ca2+]i induced by thrombin, PAF, ATP, UTP, iloprost and cicaprost were pertussis toxin-insensitive, whereas the increases induced by PGE2 and sulprostone were completely inhibited by the toxin. The increase in [Ca2+]i induced by PGE1 was partially inhibited by pertussis toxin. PGE2 did not desensitize the increase in [Ca2+]i induced by iloprost, and vice versa. PGE1 desensitized the response to PGE2 and iloprost but not vice versa. Adrenaline potentiated the iloprost- but not the PGE2-induced rise in [Ca2+]i. The phorbol ester phorbol 12-myristate 13-acetate completely blocked the rise in [Ca2+]i induced by ATP and PGE1, whereas the increases induced by thrombin and PAF were only partially inhibited. Agonists increased [Ca2+]i through release from internal stores and sustained Ca2+ influx. Thrombin stimulated Mn2+ influx, which was blocked by Ni2+. Diltiazem, isradipine, gramicidin and 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365) did not affect agonist-induced rises in [Ca2+]i. HEL cells contained substantial amounts of beta-glucuronidase which, however, could not be released, and they did not aggregate or generate superoxide. Our data suggest that: (1) HEL cells possess nucleotide receptors with properties similar to those of phagocytes; (2) they possess receptors for PGE2 and PGI2, and PGE1 is an agonist at both receptors; (3) agonist-induced increases in [Ca2+]i are mediated through pertussis toxin-sensitive as well as -insensitive signal transduction pathways; and (4) agonists increase [Ca2+]i by mobilization from internal stores and influx from the extracellular space through cation channels with properties similar to those of phagocytes and platelets.
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PMID:Receptor-mediated increases in cytosolic Ca2+ in the human erythroleukaemia cell line involve pertussis toxin-sensitive and -insensitive pathways. 131 May 89

We recently reported the characterization of a platelet granule membrane protein of molecular weight (mol wt) 40,000 called granulophysin (Gerrard et al: Blood 77:101, 1991), identified by a monoclonal antibody (MoAb D545) raised to purified dense granule membranes. Using immunoelectron-microscopic techniques on frozen thin sections, this protein was localized in resting and thrombin-stimulated platelets. In resting platelets, labeled with antigranulophysin antibodies and immunogold probes, label was localized to the membranes of one or two clear granules per platelet thin section. D545 also labeled dense granules in permeabilized whole platelets and isolated dense granule preparations examined by whole-mount techniques. Expression of granulophysin on the platelet surface paralleled dense granule secretion as measured by 14C-serotonin release under conditions in which lysosomal granule release, as measured by beta-glucuronidase secretion, was less than 5%. After thrombin stimulation, both the surface-connected canalicular system and the plasma membrane were labeled, demonstrating redistribution of granulophysin associated with degranulation. Double labeling experiments with D545 and antibodies to the alpha-granule membrane protein, P-selectin, demonstrated labeling of both P-selectin and granulophysin on dense granule membranes. Distribution of both proteins on the plasma membrane after platelet stimulation was similar. The results demonstrate that granulophysin is localized to the dense granules of platelets and is redistributed to the plasma membrane after platelet activation.
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PMID:Platelet dense granule membranes contain both granulophysin and P-selectin (GMP-140). 137 48

We showed by immunofluorescence, immunoelectron microscopy and Western blot analysis that the plasma glycoprotein (gp60), an Fc gamma binding protein which inhibits complement-mediated prevention of immune precipitation, is present in platelets. The gp60 content of platelets in normal individuals and patients with rheumatoid arthritis was similar (mean 0.028 and 0.024 fg/platelet respectively). Immunoelectron microscopic studies showed that gp60 was present in the cytoplasm and the surface connecting structures but not in the alpha granules, dense granules or lysosomes. Using this technique gp60 was also found on platelet membranes, an observation which was confirmed by immunofluorescence. Activation of platelets with thrombin, calcium ionophore, and immune complexes (IC) resulted in the release of the contents of the alpha granules (beta-thromboglobulin), dense granules (5-hydroxytryptamine) and lysosomes (beta-glucuronidase) but did not induce gp60 secretion. The inability of Fab anti-gp60 to inhibit IC-mediated platelet aggregation and of F(ab')2 anti-gp60 to produce platelet aggregation suggested that IC-mediated platelet aggregation did not occur as a result of the interaction of IC with platelet gp60. However, as the preincubation of IC with purified gp60 produced dose-dependent inhibition of the ability of IC to aggregate platelets it is possible that fluid-phase plasma gp60 modulates the interaction of IC with platelets.
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PMID:Immunohistochemical and functional studies of glycoprotein 60 (gp60) in platelets. 157 4

Administration of a single oral dose of the malathion impurity, O,O,S-trimethyl phosphorothioate (OOS-Me) or O,S,S-trimethyl phosphorodithioate (OSS-Me), to the rat resulted in hemostatic disorders, e.g. prolongation of blood clotting, prothrombin and thrombin time. Deficiency of coagulation Factors II, V and VII was also observed. OOS-Me and OSS-Me also caused dose-dependent increases of beta-glucuronidase in the blood with a maximum of 15- and 31-fold observed following treatment with 60 mg/kg OOS-Me and 40 mg/kg OSS-Me, respectively. Analysis of serum beta-glucuronidase by isoelectrofocusing electrophoresis showed that the liver endoplasmic reticulum was the source of this enzyme released into the blood. Co-treatment of OOS-Me with 5% O,O,O-trimethyl phosphorothioate (OOO-Me), a potent antagonist of OOS-Me-induced delayed toxicity, prevented hemostatic disorders but had no effect in reducing beta-glucuronidase levels. However, pretreatment of rats with piperonyl butoxide reduced the amount of beta-glucuronidase released into the blood. Of other O,O,S-trialkyl phosphorothioates examined, the O,O-diethyl S-alkyl phosphorothioates showed the highest activity in increasing beta-glucuronidase levels.
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PMID:Liver damage induced in rats by malathion impurities. 235 69

A summarizing survey of different studies in atopic eczema involving three types of cells (platelets, neutrophils, basophils) and their mediators is given. Platelets were found to release normal amounts of serotonin upon stimulation with epinephrine, thrombin and slightly reduced amounts after aggregated IgG stimulation. Serotonin uptake by washed platelets was found to be slower in atopics than in normals. Neutrophils showed a decreased release of beta-glucuronidase to stimuli like zymosan or aggregated IgG in atopics compared to controls. This might be regarded as a contributory factor to the well-known decreased resistance to infections observed in atopic eczema. Basophils in most studies released increased amounts of histamine in the atopic population compared to controls, especially after stimulation with anti-IgE. Concomitantly to the histamine release there was a slight increase in prostaglandin E2 production both in atopics and normals, which was increased by preincubation with reduced glutathion-a coenzyme of PGE2 isomerase. Histamine release tended to occur faster in atopics. Two possible factors influencing releasability characteristics were studied, namely the cyclic nucleotide system and arachidonic acid (AA) dependent mechanisms. Leucocytes of atopics showed a decreased response of cAMP to beta-adrenergic and an increased response of cGMP to cholinergic stimulation. Significant augmentation of anti-IgE-induced histamine release was observed after cholinergic stimulation. AA metabolites obviously play a regulating role in mediator release. PGE2 inhibited histamine release to various stimuli both in atopics and in normals. Indomethacin enhanced histamine release, especially after anti-IgE stimulation in atopics, while it inhibited complement-dependent release reactions both in atopics and in normals. The exogenous inhibitors of lipoxygenase eicosatetraynoic acid (ETYA) and nordihydroguaretic acid (NDGA) inhibited histamine release equally in atopics and normals. The endogenous lipoxygenase inhibitor 15-HETE showed no inhibitory but rather a slight enhancing effect upon histamine release. It is concluded that patients with atopic eczema often exhibit altered releasability patterns to a variety of stimuli. On the basis of our findings we describe "altered releasability" as one factor of a vicious cycle between increased IgE-production, mediator secretion and T cell regulatory disturbances in the pathogenesis of atopic eczema.
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PMID:Altered releasability of vasoactive mediator secreting cells in atopic eczema. 240 33

Platelets, basophils and neutrophils from a patient with the Wiskott-Aldrich syndrome (WAS) were exposed to stimuli that activate specific membrane receptor or directly initiate biochemical events (e.g. the Ca2+ ionophore A23187 and ionomycin or arachidonic acid). Platelets from this patient did not aggregate in response to ADP, collagen, thrombin or adrenaline, which activate specific membrane receptors. Platelet aggregation, however, was normal in response to compound A23187, ionomycin or exogenous arachidonic acid. Histamine release from basophils of the WAS patient was normal in response to anti-IgE, a formylated peptide (f-met peptide), and to A23187. Similarly, the release of the lysosomal enzymes, beta-glucuronidase and lysozyme, from neutrophils of the WAS patient in response to serum treated zymosan (Zx), f-met peptide, and A23187 was not significantly different from that of his parents and 13 normal donors. These results suggest that the primary defect in WAS is selectively present in platelets and is located in a biochemical step between receptor activation and Ca2+ influx and/or initiation of arachidonate metabolism.
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PMID:The Wiskott-Aldrich syndrome: studies of platelets, basophils and polymorphonuclear leucocytes. 242 57

Agents that act as anion channel blockers (ACBs) and do not permeate cells appear to inhibit exocytosis in platelets, parathyroid cells, and neutrophils. Based in large part on these observations, anion influx through plasma membrane channels has been considered a factor controlling cellular secretion, but there have been no direct anion influx measurements in cells or granules to support this concept. We have found that ACBs inhibit only thrombin-induced platelet secretion, not secretion induced by ADP, collagen, or A23187. ACBs inhibit thrombin esterolytic activity, binding of thrombin to platelets, and thrombin-stimulated platelet production of malondialdehyde in proportion to the degree of inhibition of thrombin-induced platelet secretion. Thus inhibition of platelet secretion by ACBs is due to inactivation of the stimulatory agonist, thrombin, and not to interference with cellular secretion per se. We have also found that previously reported inhibition of secretion of parathyroid cells and neutrophils by ACBs can be explained by the ability of ACBs to interfere with detection of the cellular secretory products that were measured to assess exocytosis. Our measurements of parathyroid hormone and beta-glucuronidase in the presence of ACBs were reduced to the same degree as the reported reduction in apparent cellular secretion produced by these agents. We conclude that plasma membrane anion channels of the type that can be blocked by ACBs such as 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid, suramin, and probenecid do not participate in cellular secretory processes. Whether other types of anion channels exist that are not affected by these ACBs and whether there are mechanisms of anion flux during secretion not dependent on channels remain open questions.
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PMID:Anion channel blockers cause apparent inhibition of exocytosis by reacting with agonist or secretory product, not with cell. 247 20

alpha-Thrombin induces a dose-dependent rapid transient increase in platelet cytosolic Ca2+ levels, coming solely from intracellular stores, since EGTA has no effect. In contrast, the post-stimulation equilibrium [Ca2+]in depends upon an influx from the extracellular milieu, and is lower in the presence of EGTA. We measured the Ca2+ transient (with Indo-1, 1-[2-amino-5-(6-carboxyindol-2-yl)-phenoxy]-2-(2'-amino-5'-methylp henoxy)- ethane-N,N,N',N'-tetraacetic acid), cytosolic alkalinization (with BCECF, 2',7-bis-(2-carboxyethyl)-5(and 6)-carboxyfluorescein), membrane depolarization (with diS-C3-(5), 3,3'-dipropylthiodi-carbocyanide iodide), and degranulation (by beta-glucuronidase release) induced in washed human platelets by 9 nM thrombin in the absence or presence of extracellular or intracellular Ca2+ chelating agents (EGTA and BAPTA, 5,5'-dimethyl-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, respectively). Platelets loaded simultaneously with 2 microM Indo-1 and 15 microM BAPTA (each as the acetoxymethyl ester) before addition of thrombin exhibited no cytoplasmic Ca2+ transient or alkalinization, no depolarization or degranulation. Replenishment of such cells with extracellular CaCl2 restored resting [Ca2+]in. Upon stimulation with 9 nM thrombin these replenished platelets exhibited no Ca2+ transient, and a slow gradual increase in [Ca2+]in from extracellular stores, a slow alkalinization and depolarization, and partial degranulation, all abolished by extracellular EGTA. Thus thrombin-induced platelet activation exhibits a biphasic Ca2+ requirement: the initial transient increase in [Ca2+]in comes from intracellular stores only, while the later steps of depolarization, alkalinization, and degranulation can proceed, albeit more slowly, if only extracellular Ca2+ is available.
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PMID:Cytoplasmic Ca2+ is necessary for thrombin-induced platelet activation. 251 Nov 90

Endothelial injury has been proposed as a feature of a wide variety of vascular diseases, and release of endothelial lysosomal hydrolases could contribute to the pathological changes seen. We have determined the relative activities of 14 glycosidases, two esterases and four peptide hydrolases in human umbilical vein endothelial cells and investigated whether known agonists of endothelial function, or materials known to modulate hydrolase secretion in other phagocytic cells, influenced the activity or secretion of these enzymes by human umbilical vein endothelial cells. Hexosaminidase, beta-galactosidase, beta-glucuronidase and alpha-iduronidase accounted for most of the measured glycosidase activity. Acid phosphatase activity greatly exceeded arylsulphatase activity, and most of the measured peptidase activity was due to acid peptidases. Optimum pH and apparent Km values were determined for the most abundant hydrolases. Exposure of human umbilical vein endothelial cells to bradykinin, thrombin or interleukin-1 resulted in negligible release of either hexosaminidase or lactate dehydrogenase (LDH), in contrast to phorbol myristate acetate, which caused a parallel, dose-dependent release of both enzymes. Treatment of these cells with calcium ionophore A23187, trypsin or platelet-activating factor, caused less than 10% release of either hexosaminidase or LDH. Agents known to modulate lysosomal enzyme secretion by other phagocytic cells failed to induce selective secretion of lysosomal enzymes by human umbilical vein endothelial cells.
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PMID:Lysosomal hydrolases of human vascular cells: response to agonists of endothelial function. 264 39


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