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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of phospholipase A2 (PLA2) and phospholipase C (PLC) in myocardial phosholipid degradation and cellular injury during reperfusion of ischemic myocardium. For this purpose, isolated rat hearts were perfused with isotopic arachidonic acid to label its membrane phospholipids. Hearts preperfused with antiphospholipase A2 (anti-PLA2) retained a significantly higher amount of radiolabel in phosphatidylcholine and phosphatidylinositol and a corresponding lower amount of radiolabel in lysophosphatidylcholine and nonesterified fatty acids (P less than 0.05) after 30 min of reperfusion following 30 min of normothermic global ischemia compared with hearts preperfused with nonimmune immunoglobulin G. In similar experiments, antiphospholipase C (anti-PLC)-treated hearts were associated with significantly (P less than 0.05) higher radiolabel in all phospholipids and lower radiolabel in diacyglycerol compared with nonimmune immunoglobulin G-treated hearts. Measurement of phospholipase activity in subcellular organelles of these hearts showed decreased PLA2 activity in cytosol, mitochondria, and microsomes of anti-PLA2-treated hearts and decreased PLC activity of microsomes in anti-PLC-treated hearts. Furthermore, both the antiphospholipases attenuated the release of creatine kinase and lactate dehydrogenase into perfusate and increased contractility as well as coronary flow in the reperfused hearts. Results of this study suggest that both PLA2 and PLC are involved in the degradation of phospholipids and cellular injury that occur during reperfusion of ischemic myocardium.
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PMID:Role of phospholipases A2 and C in myocardial ischemic reperfusion injury. 200 Sep 82

Non-hydrolysable analogues of phosphatidylinositol were synthesized and tested as inhibitors of phosphatidylinositol-specific phospholipase C from Bacillus cereus. In these molecules, the phosphodiester bond of phosphatidylinositol hydrolyzed by the phospholipase was replaced by a phosphonate linkage and a simpler hydrophobic group replaced the diacylglycerol moiety. One of the phosphonates also contained a carboxylate functional group suitable for matrix attachment. All three synthetic phosphonates inhibited the phospholipase C activity in a concentration-dependent manner, with the analogue most closely resembling the structure of the natural substrate, phosphatidylinositol, being the most potent inhibitor. The data indicate that phosphonate analogues of phosphatidylinositol may be useful for study of phospholipase C and other proteins interacting with myo-inositol phospholipids.
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PMID:Inhibition of phosphatidylinositol-specific phospholipase C by phosphonate substrate analogues. 210 49

A new method for the purification of phospholipase-C (phosphatidylcholine cholinephosphohydrolase, EC 3.1.4.3) from Bacillus cereus has been developed, based on its affinity to 2-(4-aminophenylsulphonyl)ethyl derivative of beaded cellulose. The enzyme was adsorbed on the affinity sorbent through a site(s) that was clearly distinct from its catalytically active site, because it was still active in the immobilized state. A possible role of enzyme-inhibitor interaction in enzyme binding to the ligand used is discussed.
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PMID:Purification of phospholipase-C from Bacillus cereus by affinity chromatography on 2-(4-aminophenylsulphonyl)ethyl-cellulose. 210 61

AD6 is a coumarin derivative which is able to inhibit platelet aggregation and release due to various agonists as adrenaline, PAF, Ca++ ionophore and others. It has been demonstrated that this compound reduces the production of free arachidonate and diglyceride from human platelets pulse-labeled with radioactive arachidonic acid thus suggesting a possible interference with the activity of phospholipase A2 and/or phospholipase C. The present report indicates that the drug has no effect on the increase of the labeling of phosphatidic acid which takes place when platelets pulse-labeled with arachidonic acid are stimulated with thrombin. Furthermore, AD6 is not able to cause changes on the metabolism of phosphoinositides monitored using platelets pre-labeled with [3H] inositol. These observations exclude the possibility that AD6 interferes with phospholipase C activity. Experiments with platelets pulse-labeled with arachidonate suggest that AD6 inhibits phospholipase(s) A2 activity or modulate negatively one or more processes involved in its activation.
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PMID:The coumarin derivative AD6 inhibits the release of arachidonic acid by interfering with phospholipase A2 activity in human platelets stimulated with thrombin. 211 Oct 85

We have previously demonstrated that influenza A virus (IAV) stimulates the human neutrophil through phospholipase C activation. With the use of the fluorescent indicator 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF), cytoplasmic acidification and subsequent alkalinization are shown to accompany this activation. These responses are not inhibited by pertussis toxin (PT). The alkalinization is mediated largely *but not entirely) by the Na(+)-H+ antiporter and is not initiated, or modulated, by the IAV-induced cytosolic Ca2+ (Cai2+) rise. Rather, protein kinase C (PKC) is likely the mediator of cell alkalinization, based on studies using the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). The acidification can be dissociated from the alkalinization response, which is also independent of Cai2+ fluxes and of PKC. Both pHi responses can be dissociated from the respiratory burst. Cytosolic alkalinization and acidification seem to reflect two independently mediated responses of the activated neutrophil, the former resulting ultimately from phospholipase activation and the latter from other activities that are not yet fully characterized.
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PMID:Human neutrophil stimulation by influenza virus: relationship of cytoplasmic pH changes to cell activation. 211 68

Changes in intracellular calcium influence epithelial barrier integrity, but the mechanism of action is unknown. One possibility is that calcium may work by increasing phospholipase A2 (PLA2) and/or phospholipase C (PLG) activity. Measuring the mannitol permeability (Pmann) of cultured monolayers of Madin-Darby canine kidney (MDCK) epithelium cells as a measure of barrier integrity, we found that exposure of the monolayers to 5 and 10 microM A23187 produced an increase in Pmann whereas 1 microM A23187 did not. Exposure of MDCK cells labeled with [3H]arachidonate to A23187 resulted in an increase in both PLA2 activity, as measured by an increase in free fatty acids, and in PLC activity, as measured by an increase in diacylglycerol (DAG). The increase in DAG was due to an increase in phosphatidylcholine-specific PLC activity. The relationship of phospholipolysis to Pmann was evaluated further by the use of mepacrine and dexamethasone. Mepacrine (10 microM) decreased PLA2 activity by 60% but had no effect on increased Pmann after exposure to A23187. Preexposure of the monolayers to dexamethasone (10 microM) blocked both PLA2 activity and PLC activity and also prevented the increase in Pmann after exposure to A23187. To evaluate whether this protective effect of dexamethasone was due to PLC blockade, we incubated the cells with the protein kinase C blocker H-7. Incubation with H-7 offered no protection from increased Pmann after A23187. These results demonstrate that increased intracellular calcium decreases the barrier integrity of epithelium and increases both PLA2 and phosphatidylcholine-specific PLC activity. The increase in Pmann, however, appears to occur through mechanisms other than phospholipase activation.
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PMID:A23187 increases permeability of MDCK monolayers independent of phospholipase activation. 211

Phospholipases and certain of their hydrolytic products are toxic to alveolar epithelial cells. Since many intracellular phospholipases are Ca2+ dependent, we postulated that elevating cytosolic Ca2+ with ionophores might cause epithelial injury via phospholipase activation. Isolated perfused hamster lungs exposed to an Ca2+ ionophore A23187 develop functional evidence of severe epithelial injury. Ultrastructural studies show widespread lysis of type I epithelial cells, with only minimal abnormalities in other lung cells, including the microvascular endothelium. Analysis of whole lung lipid extracts reveals a modest elevation in free arachidonic acid but no changes in other putative products of phospholipase activity. Parallel studies were performed in cultured cells of pulmonary origin. As measured by 51Cr release, A23187 causes substantial cytotoxicity in 3-day-old cultures of rat type II alveolar epithelial cells (RAEC) but not in cultured bovine pulmonary artery endothelial cells (BPAEC). RAEC prelabeled with [14C]stearic acid [( 14C]SA) and [3H]arachidonic acid [( 3H]AA) release radiolabeled free fatty acids (FFA) in response to A23187 in a dose- and time-dependent manner that parallels the cytotoxicity index. Analyses of putative phospholipase products in cells radiolabeled with [14C]SA and [3H]AA, with [14C]choline, or with [14C]ethanolamine suggest that liberation of radiolabeled FFA may be due to several phospholipases but with principal activity being exhibited by a phospholipase C having specificity toward phosphatidylcholine and phosphatidylethanolamine. Prelabeled BPAEC release only minimal quantities of FFA in response to A23187 under the same conditions. These studies demonstrate that elevations of intracytoplasmic Ca2+ are capable of severely and selectively damaging alveolar epithelial cells and that the injury is associated with activation of intracellular phospholipases. These findings may have implications in regard to the pathogenesis of acute lung injury in humans.
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PMID:Calcium ionophores injure alveolar epithelial cells: relation to phospholipase activity. 212 22

Cholera toxin (CT) stimulated phospholipase activity and caused [3H]arachidonic acid (3H-AA) release in a murine macrophage/monocyte cell line. Pretreatment of cells with dexamethasone, a phospholipase A2 (PLA2) inhibitor, did not affect CT-induced 3H-AA release. In contrast, aspirin, which is an inhibitor of phospholipase C (PLC), blocked CT-induced 3H-AA release and subsequent prostaglandin (PC) synthesis. The inhibitory effect of aspirin was dose dependent, with 4 mM reducing the CT response by approximately 50%. Similarly, inhibition was time dependent, occurring when the drug was added to the culture medium as late as 30 min after CT. Brief exposure (30 min) of the cells to aspirin did not alter their subsequent response to CT, but 3H-AA release from cells exposed to aspirin for 2.5 h was irreversibly inhibited. The data suggested that CT stimulation of AA metabolism may involve increased PLC activity.
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PMID:Inhibitory effect of aspirin on cholera toxin-induced phospholipase and cyclo-oxygenase activity. 212 14

Renal dipeptidase (EC 3.4.13.11) has been purified from human kidney cortex by affinity chromatography on cilastatin-Sepharose following solubilization with either n-octyl-beta-D-glucopyranoside or bacterial phosphatidylinositol-specific phospholipase C (PI-PLC). Phase separation in Triton X-114 revealed that the detergent-solubilized form was amphipathic and retained the glycosyl-phosphatidylinositol membrane anchor whereas the phospholipase solubilized form was hydrophilic. Both forms of the enzyme existed as a disulphide-linked dimer of two identical subunits of Mr 59,000 each. The glycosyl-phosphatidylinositol anchor of purified human renal dipeptidase was hydrolysed by a range of bacterial PI-PLCs and by a plasma phospholipase D. Mild acid treatment and nitrous acid deamination of the hydrophilic form revealed that the cross-reacting determinant, characteristic of the glycosyl-phosphatidylinositol anchor, was due exclusively to the inositol 1,2-cyclic phosphate ring epitope. The N-terminal amino acid sequences of the amphipathic and hydrophilic forms were identical, locating the membrane anchor at the C-terminus. The N-terminal sequence of human renal dipeptidase showed a high degree of similarity with that of the pig enzyme, and enzymic deglycosylation revealed that the difference in size of renal dipeptidase between these two species is due almost entirely to differences in the extent of N-linked glycosylation.
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PMID:Characterization of the glycosyl-phosphatidylinositol-anchored human renal dipeptidase reveals that it is more extensively glycosylated than the pig enzyme. 213 35

Despite significant advances in past years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of the actions of insulin. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Because the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second-messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure, and is produced by the insulin-sensitive hydrolysis of a glycosylphosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidylinositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion may be released from cells by a similar insulin-sensitive phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl phosphatidylinositols in insulin action.
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PMID:Second messengers of insulin action. 213 71


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