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)

Piriprost and nordihydroguiaretic acid (NDGA), specific inhibitors of arachidonate lipoxygenase, inhibited phytohaemagglutinin (PHA)-stimulated breakdown of inositol lipids in human T lymphocytes. The dual inhibitors eicosatetraynoic acid (ETYA) and BW 755C, which inhibit both lipoxygenase and cyclooxygenase, also had similar actions, whereas indomethacin and acetylsalicyclic acid, which inhibit cyclooxygenase alone, did not. The effects of lipoxygenase inhibitors and dual inhibitors were reversible. These agents did not inhibit phosphatidylinositol-4,5-bisphosphate-specific phospholipase C (PIP2-PLC) in vitro. Bromophenacyl bromide, and irreversible inhibitor of phospholipase A2, also abolished PHA-stimulated inositol lipid breakdown without affecting PIP2-PLC in vitro. The results are consistent with a role for the PHA-stimulated generation of arachidonic acid and its conversion to lipoxygenase metabolites (e.g. leukotrienes and/or hydroxyeicosatetraenoic acids) as intermediate steps in the signal transduction pathway between cell-surface mitogen receptors and the stimulation of PIP2-PLC in lymphocytes.
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PMID:Inhibitors of arachidonic acid lipoxygenase impair the stimulation of inositol phospholipid hydrolysis by the T lymphocyte mitogen phytohaemagglutinin. 255

We have examined effects of quaternary ammonium compounds on the in vitro degradation of endogenous lipids in isolated lysosomes. The degree of lipid degradation was assessed by determining hydrolysis products of labeled lipid. Lipolysis was inhibited by quaternary ammonium compounds. The degrees of inhibition were as follows: ethidium bromide greater than N-methylatropinium bromide (NMA) greater than tubocurarine. The inhibition of lipolysis by these quaternary ammonium compounds is not necessarily correlated with the differences in their polarities, molecular weight or structures. The degradation of three phospholipid classes was inhibited by NMA with phosphatidylcholine the most vulnerable. The effect of NMA on the hydrolysis of [14C]dipalmitoylphosphatidylcholine (phospholipid) by lysosomal soluble proteins was also examined. The effect of NMA on phospholipase A1 was assessed by the formation of lysophosphatidylcholine, and that on phospholipase C was assessed as the sum of mono- and diglyceride formations. The action of NMA on the phospholipid degradation was similar to that of cationic amphiphilic drugs, but it differed somewhat from that of chloroquine for each enzyme. From these results, it was concluded that one of the inhibitory mechanisms of phospholipid degradation by NMA was the direct interaction between NMA and phospholipase A1 or C.
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PMID:Effects of quaternary ammonium compounds on the degradation of lipids in lysosomes. 274 50

Bath application of the inhibitors of phospholipases, nordihydroguaiaretic acid (NDGA) and p-bromo-phenacyl bromide (BPB), to the rat hippocampal slices suppressed long-term potentiation (LTP) in Schaffer/commissural-CA1 pyramidal synapses. On the other hand, neither of the two inhibitors suppressed LTP in mossy fiber-CA3 pyramidal cell synapses. BPB did not suppress phosphatidylinositol-specific phospholipase C (PI-PLC) activity of the slices. These results suggested that the mechanisms of LTP were quite different in the CA1 and CA3 subfields of rat hippocampus: in CA1, the involvement of an arachidonate metabolism was strongly suggested, whereas in CA3, an arachidonic acid cascade may not be necessary for LTP.
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PMID:Differential effects of phospholipase inhibitors in long-term potentiation in the rat hippocampal mossy fiber synapses and Schaffer/commissural synapses. 276 61

Large unilamellar vesicles composed of phosphatidylcholine/phosphatidylethanolamine/cholesterol (50:25:25 mole ratio) were treated with phospholipase C. The early stages of phospholipid cleavage are accompanied by mixing of bilayer lipids (monitored by dequenching of octadecylrhodamine fluorescence) and leakage-free mixing of vesicle contents [measured by using 8-aminonaphthalene-1,3,6-trisulfonic acid (ANTS) and p-xylylenebis(pyridinium bromide) (DPX)]. These results are interpreted in terms of vesicle fusion induced by the catalytic activity of phospholipase C. The use of sonicated unilamellar vesicles decreases the lag time, but does not modify the amplitude, of the fusion process. The presence of both phosphatidylethanolamine and cholesterol appears to be essential for measurable fusion effects to occur with low levels of phospholipid hydrolysis. Optimal fusion rates are observed with about 10-20 enzyme molecules per large unilamellar vesicle. This system of catalytically induced liposome fusion may be of relevance for the interpretation of physiological membrane fusion processes.
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PMID:Liposome fusion catalytically induced by phospholipase C. 281 74

We have used mixed- and co-cultures of endothelial and vascular smooth muscle cells to investigate the role of phospholipase activation and arachidonic acid metabolites in the production of endothelium-derived relaxing factor (EDRF). Inhibition of phospholipase A2 with para-bromophenacyl bromide, dexamethasone or quinacrine, alone or in combination, blocked arachidonate release by 50%-60% but had no effect on EDRF production as assessed by cyclic GMP accumulation in mixed- or co-cultures of endothelial and vascular smooth muscle cells. Inhibition of the phospholipase C-diacylglycerol (DAG) lipase pathway of arachidonate release by the DAG lipase inhibitor RHC-80267 also caused partial inhibition of arachidonate release and had no effect on EDRF. When both phospholipase A2 and phospholipase C pathways for arachidonate mobilization were inhibited (dexamethasone + RHC 80267), arachidonate release was totally inhibited while EDRF release remained intact. We conclude that neither phospholipase activation nor arachidonate mobilization is required for EDRF release from cultured bovine endothelial cells.
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PMID:Use of cultured cells to study the relationship between arachidonic acid and endothelium-derived relaxing factor. 283 49

The stimulation of the human neutrophil NADPH-oxidase is initiated by a variety of agonists, which appear to utilize more than one activation pathway. We have discerned that opsonized zymosan (OZ) stimulates O2- release by a mechanism distinct from that of phorbol myristate acetate (PMA). PMA differs from OZ stimulation in its susceptibility to H-7 (a protein kinase inhibitor) inhibition of O2- release and the lack of PMA-initiated release of radiolabeled arachidonic acid ([3H]AA) from prelabeled cells. That AA release was linked to O2- generation in OZ-stimulated cells was suggested by the finding that mepacrine, a phospholipase inhibitor, exhibits parallel dose response inhibition for both O2- generation and [3H]AA release, whereas mepacrine did not significantly inhibit the O2- generation induced by PMA. The specific involvement of phospholipase A2 (PLA2) in the release of AA was indicated by the lack of release of [3H]oleate, which is not released by PLA2 in intact cells; [3H]AA released from phosphatidylinositol and phosphatidylcholine and not accompanied by the formation of [3H]-arachidonyl phosphatidic acid, thus eliminating the involvement of phospholipase C; and the inhibition of [3H]AA release by p-bromophenacyl bromide, a specific PLA2 inhibitor. The reduction of O2- formation by inhibitors of AA metabolism (BW755C, acetylsalicylic acid, and indomethacin) further supports a linkage between AA release and O2- generation. That [3H]AA release, like O2- generation, in OZ-stimulated cells was calcium dependent further differentiates OZ from calcium-independent PMA activation. These studies in toto suggest that OZ stimulation of the NADPH-oxidase differs from PMA, in that the particulate stimulus is PLA2 mediated and independent of protein kinase C.
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PMID:Identification of distinct activation pathways of the human neutrophil NADPH-oxidase. 302 Jan 28

A novel method for studying the mobilization of free arachidonic acid (AA) in isolated intestinal epithelial cells is described. The method is based on labeling the cellular phospholipids with 14C-AA and studying the release of this 14C-AA on subsequent phospholipase activation. Cells of high viability were isolated from the small intestine of guinea pigs and incubated with 14C-AA for 2 h; most of the incorporated 14C-AA was then esterified into phosphatidylethanolamine and phosphatidylcholine. When the labeled cells were stimulated with the calcium ionophore A23187 in the presence of external calcium, they released significant amounts of AA. In contrast, the cells released no AA when stimulated with A23187 in the absence of external calcium or in the presence of chlorpromazine or 4-bromophenacyl bromide, both of which are known to inhibit phospholipase A2 activity. On the other hand, the cells released significant AA in response to exogenous phospholipase C from Clostridium perfringens. These findings indicate that AA release in intestinal cells may be caused by calcium-mediated phospholipase A2 activation or by products of microbial phospholipase C activity. They also suggest the further use of 14C-AA-labeled cells for studying agents and mechanisms that may influence the release of AA in the gastrointestinal tract.
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PMID:Phospholipase activation and arachidonic acid release in isolated intestinal epithelial cells. 313 36

The neural cell adhesion molecule L1 is a phosphorylated, integral membrane glycoprotein that is recovered from adult mouse brain tissue by immunoaffinity chromatography as a set of polypeptides with apparent molecular masses of 200, 180, 140, and 80 kilodaltons (L1-200, L1-180, L1-140, and L1-80, respectively). It has been shown that L1-140 and the phosphorylated L1-80 is generated from L1-200 by mild proteolytic treatment of intact cells. In the present study we have investigated the structural relationships between the different molecular forms of L1 and their location with regard to the surface membrane. We could show that L1-200 has two preferred cleavage sites, one that generates the amino terminal, extracellularly exposed L1-140 and the carboxy terminal L1-80 that spans the membrane. Cleavage at the other site leads to the generation of the amino terminally located L1-180 and the membrane-attached, phosphorylated carboxy terminal L1-30. This site is cleaved during treatment of live cultured cells with broad-spectrum, protease-free phospholipase C (but not phosphatidylinositol-specific phospholipase C) or exposure to sodium azide or cyanogen bromide. Other conditions that cause damage to cells do not lead to the generation of L1-180 and L1-30, suggesting a particular cell-intrinsic cleavage mechanism. L1-180 is truly soluble in aqueous solutions, since it can be recovered from culture supernatants and in the supernatant of a crude membrane fraction after incubation for 2 h at 37 degrees C. Although trypsin treatment alone does not release L1-140 into the supernatant, combination of phospholipase C and mild tryptic treatment leads to the release of L1-140 and L1-50, the latter being most likely the extracellularly exposed domain of L1-80 that is complementary to the membrane-integrated phosphorylated L1-30. Phase separation experiments with Triton X-114 show that the released forms of L1-180 and L1-140 distribute into the aqueous phase, whereas they distribute into the detergent phase when in association with L1-200 or L1-80. However, when L1-80 is cleaved to yield the soluble L1-50 and membrane-anchored L1-30, L1-140 is released into the supernatant together with L1-50. A strong affinity of L1-200, L1-140, and L1-80 to each other is also indicated by the fact that they incorporate together into liposomes and separate only under strong detergent conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical characterization of different molecular forms of the neural cell adhesion molecule L1. 327 40

The gene coding for protein A (spa) of Staphylococcus aureus 8325-4 has been inactivated by substituting part of the spa coding sequence for a DNA fragment specifying resistance to ethidium bromide. The in vitro-constructed spa::EtBrr substitution mutation was introduced into the S. aureus chromosome by recombinational allele replacement. Southern blot hybridization showed that the in vitro-constructed mutation was present in the chromosomal spa locus. We have previously reported the inactivation of the alpha-toxin gene (hly) by allele replacement with an in vitro-constructed hly::Emr (erythromycin resistance) mutation (M. O'Reilly, J.C.S. de Azavedo, S. Kennedy, and T.J. Foster, Microb. Pathogen. 1:125-138, 1986). A double Spa- Hly- mutant was constructed by transduction. The virulence of Spa- and Hly- mutants was tested by experimental infection of mice. When subcutaneous injections were given, Hly- mutants formed a flat, darkened lesion, whereas Hly+ strains caused a raised, cream lesion. Alpha-toxin was shown to be a major factor in forming subcutaneous lesions and in causing the death of mice injected intraperitoneally. Spa- mutants were slightly less virulent than their Spa+ counterparts, which suggests that protein A is also a virulence factor of S. aureus.
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PMID:Virulence of protein A-deficient and alpha-toxin-deficient mutants of Staphylococcus aureus isolated by allele replacement. 367 45

We have investigated the effects of phospholipase A2 and C on the synthesis of prostaglandin E2 in rabbit kidney medulla and the release of fatty acids from the medulla slices. Exogenous phospholipase A2 [from Naja naja (Indian cobra) venom] and phospholipase C (from Clostridium welchii) stimulated prostaglandin E2 production in a dose-dependent manner. At the maximal effective concentrations (0.5 unit of phospholipase A2/ml, 2 units of phospholipase C/ml), phospholipase C increased prostaglandin E2 formation to the level observed with phospholipase A2. Phospholipase A2 enhanced the release only of unsaturated fatty acids, whereas phospholipase C stimulated the release of individual free fatty acids (C 16:0, C 18:0, C 18:1, C 18:2 and C 20:4). Moreover, p-bromophenacyl bromide inhibited phospholipase A2-stimulated prostaglandin E2 production and the release of fatty acids, but it had no influence on prostaglandin E2 formation and the release of fatty acids increased by phospholipase C, indicating that the stimulatory effect of phospholipase C is not mediated through the activation of endogenous phospholipase A2. These results suggest the presence of diacylglycerol lipase and monoacylglycerol lipase in the kidney and the importance of this pathway in prostaglandin synthesis by the kidney.
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PMID:Stimulation of prostaglandin E2 synthesis by exogenous phospholipase A2 and C in rabbit kidney medulla slices. 658 1


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