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)

Mucolipidosis (ML) II and III are rare autosomal recessively inherited diseases characterized by deficiency of multiple lysosomal enzymes and, as a result, a generalized storage of macromolecules in lysosomes of cells of mesenchymal origin. In ML II and ML III fibroblasts, most, but not all, newly synthesized lysosomal enzymes are secreted into the medium instead of being targeted correctly to lysosomes. Defects in the enzyme UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase underlie this effect. It is unknown how lysosomal phospholipases are targeted to the lysosomes of fibroblasts. In the present study lysosomal phospholipase activity was determined in delipidated fibroblast homogenates and plasma from ML II and ML III patients and controls using a [3H]choline-labeled phosphatidylcholine. After incubation, residual phosphatidylcholine and its labeled degradation products (lysophosphatidylcholine, glycerophosphorylcholine and choline phosphate) were quantified. We found that ML II and ML III fibroblasts are deficient in lysosomal phospholipase A and C activity. These enzymes were present in elevated amounts in plasma of ML II and ML III patients. These data indicate that phospholipases, like most other lysosomal enzymes in these diseases, are secreted into the blood instead of being targeted specifically to lysosomes. Thus, the mannose-6-phosphate receptor pathway is needed for proper delivery of lysosomal phospholipases to lysosomes. We also found that production of labeled choline phosphate was mainly due to the activity of acid sphingomyelinase instead of phospholipase C under the assay conditions used. Other active lipolytic enzymes were phospholipase A and lysophospholipase. No evidence for phospholipase D activity was found.
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PMID:Lysosomal phospholipase activity is decreased in mucolipidosis II and III fibroblasts. 998 67

A 16 kDa Schistosoma mansoni schistosomular surface antigen (Sm16) was originally described as the target of a passively protective mAb (B3A). It appeared on the schistosomular surface after transformation of cercariae and was uniquely recognised by sera from animals exposed to attenuated cercariae. In this work sequential extractions of schistosomula with Triton X-114 and sodium dodecyl sulphate showed Sm16 to be an integral membrane structure which did not appear to be glycosylphosphatidylinositol-anchored as judged by experiments using phosphatidyl inositol-specific phospholipase C. The antigen was strongly reactive in Western blotting with rabbit irradiated vaccine sera. Sm16 was demonstrated in the hepatopancreas of S. mansoni-infected snails and was equally abundant in cercariae and mechanically- transformed schistosomula but was undetected in liver stage worms or eggs. Immunoelectron microscopy showed Sm16 to be localised, in cercariae, to what are believed to be subtegumental cell bodies packed with membraneous vesicles. Treatment with proteases and with sodium metaperiodate showed Sm16 to be a glycoprotein of which the epitope recognised by B3A was periodate sensitive. Two-dimensional electrophoresis gave a PI of 6. Neither the size or the recognition by B3A was affected by treatment with N-glycosidase F, endoglycosidase F or endo-alpha-N-acetylgalactosaminidase. Western blotting using a wide range of biotinylated lectins showed recognition only by peanut agglutinin and Ricinus communis agglutinin II (ricin). It is concluded that Sm16 has antigenic surface-exposed O-linked complex oligosaccharides which lack mannose/glucose, GlcNAc, L-fucose and sialic acid but contain terminal Gal beta (1-3) GalNAc and/or galactose.
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PMID:Characterization of a stage-specific Mr16000 schistosomular surface glycoprotein antigen of Schistosoma mansoni. 1037 96

Strong phospholipase A (PLA) and phospholipase C (PLC) activities as potential virulence factors are the outstanding characteristics of eight strains of small oral spirochaetes isolated from deep periodontal lesions. By qualitative dot-blot DNA-DNA hybridization and 16S rDNA sequence comparison, these spirochaetes form a distinct phylogenetic group, with Treponema maltophilum as its closest cultivable relative. Growth of these treponemes, cells of which contain two endoflagella, one at each pole, was autoinhibited by the PLA-mediated production of lysolecithin unless medium OMIZ-Pat was prepared without lecithin. N-Acetylglucosamine was essential and D-ribose was stimulatory for growth. All isolates were growth-inhibited when 1% foetal calf serum was added to the medium. Growth on agar plates supplemented with human erythrocytes produced haemolysis. In addition to PLA and PLC, the new isolates displayed strong activities of alkaline and acid phosphatases, beta-galactosidase, beta-glucuronidase, N-acetyl-beta-glucosaminidase and sialidase, intermediate activities of C4- and C8-esterases, naphthol phosphohydrolase and alpha-fucosidase and a distinctive 30 kDa antigen detectable on Western blots. This phenotypically and genotypically homogeneous group is proposed as a novel species, Treponema lecithinolyticum sp. nov., with isolate OMZ 684T designated as the type strain. A molecular epidemiological analysis using a T. lecithinolyticum-specific probe showed this organism to be associated with affected sites when compared with unaffected sites of periodontitis patients. This association was more pronounced in patients with rapidly progressive periodontitis than in those with adult periodontitis.
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PMID:Treponema lecithinolyticum sp. nov., a small saccharolytic spirochaete with phospholipase A and C activities associated with periodontal diseases. 1055 10

Aerolysin of the Gram-negative bacterium Aeromonas hydrophila consists of small (SL) and large (LL) lobes. The alpha-toxin of Gram-positive Clostridium septicum has a single lobe homologous to LL. These toxins bind to glycosylphosphatidylinositol (GPI)-anchored proteins and generate pores in the cell's plasma membrane. We isolated CHO cells resistant to aerolysin, with the aim of obtaining GPI biosynthesis mutants. One mutant unexpectedly expressed GPI-anchored proteins, but nevertheless bound aerolysin poorly and was 10-fold less sensitive than wild-type cells. A cDNA of N-acetylglucosamine transferase I (GnTI) restored the binding of aerolysin to this mutant. Therefore, N-glycan is involved in the binding. Removal of mannoses by alpha-mannosidase II was important for the binding of aerolysin. In contrast, the alpha-toxin killed GnTI-deficient and wild-type CHO cells equally, indicating that its binding to GPI-anchored proteins is independent of N-glycan. Because SL bound to wild-type but not to GnTI-deficient cells, and because a hybrid toxin consisting of SL and the alpha-toxin killed wild-type cells 10-fold more efficiently than GnTI- deficient cells, SL with its binding site for N-glycan contributes to the high binding affinity of aerolysin.
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PMID:Requirement of N-glycan on GPI-anchored proteins for efficient binding of aerolysin but not Clostridium septicum alpha-toxin. 1235 21

Tumor necrosis factor-alpha (TNF-alpha) binds to TNF-alpha receptors (TNFR) to produce a hexameric (TNF-alpha)(3)-(TNFR)(3) structure that stimulates apoptosis. We found by using ELISA that TNF-alpha binds to the glycosylphosphatidylinositol (GPI) anchor glycans of carcinoembryonic antigen, human placental alkaline phosphatase (hAP), and Tamm-Horsfall glycoprotein. These binding abilities were inhibited by 10(-6)M mannose-6-phosphate. Treatment of hAP with mild acid and phosphatase, which releases the N-acetylglucosamine (GlcNAc) beta1 -->phosphate-->6 residue from the GPI-anchor glycan of hAP, abrogated the binding of TNF-alpha to hAP. Thus, TNF-alpha binds to the GlcNAcbeta1-->phosphate-->6Man residue in GPI-anchor glycans. To investigate whether the carbohydrate-binding ability of TNF-alpha is related to its physiological functions, human lymphoma U937 cells were used. TNF-alpha stimulates U937 cell apoptosis in a dose-dependent manner and the presence of mannose-6-phosphate inhibited this. TNF-alpha-dependent tyrosine phosphorylation of several proteins in U937 cells was also diminished by mannose-6-phosphate. Phosphatidylinositol-specific phospholipase C-pretreatment also inhibited this tyrosine phosphorylation. These data suggest that TNF-alpha stimulates U937 cell apoptosis by forming a high-affinity nanomeric (TNF-alpha)(3)-(TNFR)(3)-(GPI-anchored glycan)(3) complex. The GPI-anchored glycoprotein involved remains to be identified.
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PMID:Recognition by TNF-alpha of the GPI-anchor glycan induces apoptosis of U937 cells. 1515 80

We report on microbore liquid chromatography (microLC) and capillary electrophoresis (CE) separation of glycopeptides and high-mannose-type oligosaccharides, digested from recombinant phospholipase C, expressed in Pichia pastoris. The glycopeptides were subject to microLC/electrospray ionization/mass spectrometry (ESI-MS) and microLC/ESI-tandem MS (MS/MS) analysis that revealed high-mannose structure size variation between Man(7)GlcNAc(2) and Man(14)GlcNAc(2). Then, high-performance CE was applied to identify possible positional isomers of the high-mannose structures. For the CE experiments, the oligosaccharides were released from the glycoproteins by peptide-N-glycosidase F and labeled with 1-aminopyrene-3,6,8-trisulfonic acid (APTS). Excellent separation of the possible positional isomers was attained, suggesting one for Man(9)GlcNAc(2), two for Man(10)GlcNAc(2), three for Man(11)GlcNAc(2), Man(12)GlcNAc(2), and Man(13)GlcNAc(2), and two for Man(14)GlcNAc(2). The CE results provided complementary information to the microLC/ESI-MS and MS/MS data with respect to the possible number of positional isomers.
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PMID:Analysis of high-mannose-type oligosaccharides by microliquid chromatography-mass spectrometry and capillary electrophoresis. 1523

Interleukin (IL)-18 induces T cells and natural killer cells to produce not only interferon-gamma but also other cytokines by binding to the IL-18 receptor (IL-18R) alpha and beta subunits. However, little is known about how IL-18, IL-18Ralpha, and IL-18Rbeta form a high-affinity complex on the cell surface and transduce the signal. We found that IL-18 and IL-18Ralpha bind to glycosylphosphatidylinositol (GPI) glycan via the third mannose 6-phosphate diester and the second beta-GlcNAc-deleted mannose 6-phosphate of GPI glycan, respectively. To determine which GPI-anchored glycoprotein is involved in the complex of IL-18 and IL-18Ralpha, IL-18Ralpha of IL-18-stimulated KG-1 cells was immunoprecipitated together with CD48 by anti-IL-18Ralpha antibody. More than 90% of CD48 was detected as beta-GlcNAc-deleted GPI-anchored glycoprotein, and soluble recombinant human CD48 without GPI glycan bound to IL-18Ralpha, indicating that CD48 is associated with IL-18Ralpha via both the peptide portion and the GPI glycan. To investigate whether the carbohydrate recognition of IL-18 is involved in physiological activities, KG-1 cells were digested with phosphatidylinositol-specific phospholipase C before IL-18 stimulation. Phosphatidylinositol-specific phospholipase C treatment inhibited the phosphorylation of tyrosine kinases and the following IL-18-dependent interferon-gamma production. These observations suggest that the complex formation of IL-18.IL-18Ralpha. CD48 via both the peptide portion and GPI glycan triggers the binding to IL-18Rbeta, and the IL-18.IL-18Ralpha.CD48.IL-18Rbeta complex induces cellular signaling.
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PMID:Functional role played by the glycosylphosphatidylinositol anchor glycan of CD48 in interleukin-18-induced interferon-gamma production. 1576 Sep 5

Here we report inhibition of phospholipase C-beta1 (PLC-beta1)-mediated signaling by post-translational glycosylation with beta-N-acetylglucosamine (O-GlcNAc modification). In C2C12 myoblasts, isoform-specific knock-down experiments using siRNA showed that activation of bradykinin (BK) receptor led to stimulation of PLC-beta1 and subsequent intracellular Ca2+ mobilization. In C2C12 myotubes, O-GlcNAc modification of PLC-beta1 was markedly enhanced in response to treatment with glucosamine (GlcNH2), an inhibitor of O-GlcNAase (PUGNAc) and hyperglycemia. This was associated with more than 50% inhibition of intracellular production of IP3 and Ca2+ mobilization in response to BK. Since the abundance of PLC-beta1 remained unchanged, these data suggest that O-GlcNAc modification of PLC-beta1 led to inhibition of its activity. Moreover, glucose uptake stimulated by BK was significantly blunted by treatment with PUGNAc. These data support the notion that O-GlcNAc modification negatively modulates the activity of PLC-beta1.
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PMID:Inhibition of phospholipase C-beta1-mediated signaling by O-GlcNAc modification. 1653 62

Using hypotonically permeabilized Toxoplasma gondii tachyzoites, we investigated the topology of the free glycosylphosphatidylinositols (GPIs) within the endoplasmic reticulum (ER) membrane. The morphology and permeability of parasites were checked by electron microscopy and release of a cytosolic protein. The membrane integrity of organelles (ER and rhoptries) was checked by protease protection assays. In initial experiments, GPI biosynthetic intermediates were labeled with UDP-[6-(3)H]GlcNAc in permeabilized parasites, and the transmembrane distribution of the radiolabeled lipids was probed with phosphatidylinositol-specific phospholipase C (PI-PLC). A new early intermediate with an acyl modification on the inositol was identified, indicating that inositol acylation also occurs in T. gondii. A significant portion of the early GPI intermediates (GlcN-PI and GlcNAc-PI) could be hydrolyzed following PI-PLC treatment, indicating that these glycolipids are predominantly present in the cytoplasmic leaflet of the ER. Permeabilized T. gondii parasites labeled with either GDP-[2-(3)H]mannose or UDP-[6-(3)H]glucose showed that the more mannosylated and side chain (Glc-GalNAc)-modified GPI intermediates are also preferentially localized in the cytoplasmic leaflet of the ER.
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PMID:Membrane topology and transient acylation of Toxoplasma gondii glycosylphosphatidylinositols. 1689 25

Sandhoff disease (SD) is a lysosomal beta-hexosaminidase deficiency involving excessive accumulation of undegraded substrates, including terminal N-acetylglucosamine-oligosaccharides and GM2 ganglioside, and progressive neurodegeneration. Our previous study demonstrated remarkable induction of macrophage inflammatory factor-1alpha (MIP-1alpha) in microglia in the brains of SD model mice as a putative pathogenic factor for SD via microglia-mediated neuroinflammation. In this study, we established microglial cell lines (WT- and SD-Mg) from wild-type and SD mice, and first demonstrated the enhanced production of MIP-1alpha in SD-Mg. Inhibitors of protein kinase C (PKC) and Akt reduced the production of MIP-1alpha by SD-Mg. Elevated activation of Akt and partial translocation of PKC isozymes (alpha, betaI, betaII, and delta) from the cytoplasm to the membrane in SD-Mg were also revealed by means of immunoblotting. Furthermore, it was demonstrated that intracellular extracellular signal-regulated kinase, c-Jun N-terminal kinase, and phospholipase C (PLC), but not phosphoinositide 3-kinase, should contribute to the induction of MIP-1alpha in SD-Mg, and that PLC could independently regulate the activation of both PKC and Akt. We proposed here that the deregulated activation of PLC should cause the enhanced MIP-1alpha production via plural signaling pathways mediated by PKC and Akt, followed by extracellular signal-regulated kinase and c-Jun N-terminal kinase, in SD-Mg.
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PMID:Abnormal production of macrophage inflammatory protein-1alpha by microglial cell lines derived from neonatal brains of Sandhoff disease model mice. 1930 85


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