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)

1. Independent of its effects on renal haemodynamics and glomerular filtration, angiotensin II (AII) has direct actions on the proximal tubule involving transepithelial Na+, H+, HCO3-, and water reabsorption, ammoniagenesis, gluconeogenesis and renal growth. 2. The effects of AII on water and electrolyte transport are biphasic and dose-dependent, such that low concentrations (10(-12)-10(-9) mol/L) stimulate reabsorption whereas high concentrations (10(-7)-10(-6) mol/L) inhibit reabsorption. Similar dose-response relations have been obtained for luminal and peritubular addition of AII. 3. The cellular responses to AII are mediated via an AT-1 receptor coupled via G-regulatory proteins to several parallel signal transduction pathways. Low doses inhibit the basolateral adenylate cyclase, lower intracellular cAMP and withdraw the inhibitory effect of protein kinase A on the luminal Na/H exchanger. Stimulation of this exchanger may also occur due to AII-receptor activation of phospholipase C to release diacyl glycerol, or by local transduction in the brush-border membrane involving phospholipase A2. 4. Inhibition of proximal fluid reabsorption is associated with increased intracellular Ca2+ released from intracellular stores, or entering via voltage-sensitive channels in response to the release of inositol-1,4,5-trisphosphate, or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6-epoxy-eicosatrienoic acid. 5. The stimulatory actions of peritubular AII on proximal transport are inhibited by physiological concentrations of atrial natriuretic factor (ANF) and by parathyroid hormone (PTH). 6. It is concluded that intrarenal AII acts to maintain optimal matching of fluid reabsorption and filtered load in response to changes in sodium balance, as well as to promote acidification of the urine during acidosis and perhaps to potentiate tubular growth following renal injury.
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PMID:Regulation of proximal tubule function by angiotensin. 151 68

Alkaline phosphatase was the first zinc enzyme to be discovered in which three closely spaced metal ions (two Zn ions and one Mg ion) are present at the active center. Zn ions at all three sites also produce a maximally active enzyme. These metal ions have center-to-center distances of 3.9 A (Zn1-Zn2), 4.9 A (Zn2-Mg3), and 7.1 A (Zn1-Mg3). Despite the close packing of these metal centers, only one bridging ligand, the carboxyl of Asp51, bridges Zn2 and Mg3. A crystal structure at 2.0-A resolution of the noncovalent phosphate complex, E.P, formed with the active center shows that two phosphate oxygens form a phosphate bridge between Zn1 and Zn2, while the two other phosphate oxygens form hydrogen bonds with the guanidium group of Arg166. This places Ser102, the residue known to be phosphorylated during phosphate hydrolysis, in the required apical position to initiate a nucleophilic attack on the phosphorous. Extrapolation of the E.P structure to the enzyme-substrate complex, E.ROPO4(2-), leads to the conclusion that Zn1 must coordinate the ester oxygen, thus activating the leaving group in the phosphorylation of Ser102. Likewise, Zn2 appears to coordinate the ester oxygen of the seryl phosphate and activate the leaving group during the hydrolysis of the phosphoseryl intermediate. Both of these findings suggest that there may be a significant dissociative character to each of the two displacements at phosphorous catalyzed by alkaline phosphatase. A water molecule (or hydroxide) coordinated to Zn1 following formation of the phosphoseryl intermediate appears to be the nucleophile in the second step of the mechanism. Dissociation of the product phosphate from the E.P intermediate is the slowest, 35 s-1, and therefore the rate-limiting, step of the mechanism at alkaline pH. Since the determination of the initial crystal structure of alkaline phosphatase, two other crystal structures of enzymes involved in phosphate ester hydrolysis have been completed that show a triad of closely spaced zinc ions present at their active centers. These enzymes are phospholipase C from Bacillus cereus (structure at 1.5-A resolution) (43) and P1 nuclease from Penicillium citrinum (structure at 2.8-A resolution) (74). Both enzymes hydrolyze phosphodiesters. Substrates for phospholipase C are phosphatidylinositol and phosphatidylcholine, while P1 nuclease is an endonuclease hydrolyzing single stranded ribo- and deoxyribonucleotides. P1 nuclease also has activity as a phosphomonoesterase against 3'-terminal phosphates of nucleotides. The Zn ions in both enzymes form almost identical trinuclear sites.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Structure and mechanism of alkaline phosphatase. 152 73

Activation of phospholipase C (PLC) is considered to be one of the cellular signaling events involved in dopamine (DA)-mediated natriuresis. In the present study we have examined the role of renal cortical PLC in contributing to the increase in urinary sodium excretion during high sodium intake and its relationship with intrarenal DA synthesis. Rats were given either 1% NaCl (high sodium intake) or tap water (normal sodium intake) to drink for 24 h, and urine was collected over this time period. PLC activity in the renal cortex from these rats was measured by prelabeling cortical slices with myo-[2-3H]inositol and was expressed as fractional release (FR) of inositol (mono-, bis-, and tris-) phosphates. Acute increase in sodium intake produced 93 +/- 8% increase over control in urinary DA excretion. These changes were accompanied by significant increases (30 +/- 8%) in basal FR of inositol phosphates and 243 +/- 40 and 76 +/- 14% increases in urinary sodium and water excretion, respectively. The elevated basal PLC activity in rats with high sodium intake was significantly reduced in the presence of Sch 23390, a selective DA-1 receptor antagonist. Exogenously added DA (3 mM) also produced significant increases in PLC activity, although the magnitudes of increases were different in rats with high (37 +/- 8%) and normal (66 +/- 9%) sodium intake. However, Sch 23390 alone or carbidopa pretreatment did not affect the basal PLC activity in rats maintained on normal sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopamine receptor-mediated activation of phospholipase C is associated with natriuresis during high salt intake. 155 66

Respiratory-gated proton magnetic resonance imaging was used to study the response of the rat liver in situ to bromobenzene, a classic hepatotoxicant. A localized region of high proton signal intensity in the perihilar region of the liver was seen 24-48 hr after an intraperitoneal injection of bromobenzene. Localized proton magnetic resonance spectra from within this region indicated that the increased proton signal intensity was not due to accumulation of fat in the liver, but primarily due to a longer T2 for the proton resonance of water. This is consistent with acute edema in this localized region. In vivo 31P magnetic resonance spectroscopy studies of the same rat livers in situ were performed. Spectroscopic conditions were determined whereby localized, quantitative 31P spectra could be obtained. Using these methods, 10 mmol/kg bromobenzene was found after 24 hr to cause a number of statistically significant (p less than 0.05) effects: a decrease in adenosine 5'-triphosphate levels from 4.1 +/- 0.5 to 3.0 +/- 0.5 mM, a decrease in phosphodiester levels from 11.3 +/- 0.9 to 9.3 +/- 0.7 mM and an increase in the phosphomonoesters from 3.0 +/- 0.4 to 5.5 +/- 1.2 mM (mean +/- standard deviation). High resolution in vitro 31P spectra of perchloric acid extracts of these rat livers showed that the increased phosphomonoester resonance was due to a selective 4.3-fold increase in phosphocholine. Thus, our in vivo and in vitro 31P magnetic resonance spectra are consistent with the hypothesis that a phosphatidylcholine-specific phospholipase C (generating phosphocholine and diacylglycerol) is activated during tissue damage. Both the imaging and spectroscopy results obtained with bromobenzene closely resemble CCl4-induced liver changes previously reported, and may reflect a generalized response of the liver to any acutely acting toxic chemical.
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PMID:Proton magnetic resonance imaging and phosphorus-31 magnetic resonance spectroscopy studies of bromobenzene-induced liver damage in the rat. 156 94

The water-soluble alpha-toxin monomers of Staphylococcus aureus become hexamers forming the transmembrane pore when exposed to the membranes. This pore is freely permeable to small hydrophilic molecules, e.g. carboxyfluorescein, and becomes less permeable in the presence of calcium ions. Calcium ion-mediated decrease of the carboxyfluorescein leakage could not be eliminated by EDTA added in the medium, but the carboxyfluorescein could be freed by EDTA added in the intraliposomal space. This result suggests that the alpha-toxin pore changes its conformation as the calcium ion is bound and that the binding site is exposed to the intraliposomal side of the membrane. The interaction between the alpha-toxin hexamer and 8-anilino-1-naphthalene-sulfonic acid (ANS) was monitored by determining the fluorescence in the presence and absence of calcium chloride. The mean distances between the tryptophan residues of the alpha-toxin hexamer and the bound ANS were calculated to be 1.90 and 1.80 nm in the absence and presence, respectively, of calcium ions. The results showed the calcium ion mediated conformational change of the membrane-embedded alpha-toxin hexamer.
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PMID:Calcium ion-mediated regulation of the alpha-toxin pore of Staphylococcus aureus. 156 91

The role of phospholipids in the function of LH/hCG receptors was studied in two receptor preparations: the membrane fraction of porcine corpora lutea (CL) and the water-soluble receptor in follicular fluid (LFF) which was characterized. Digestion of CL membranes with phospholipase C (PL-C) abolished, in a dose responsive manner, specific binding of [125I]hCG and decreased phospholipid concentrations in the membranes. This loss of LH/hCG receptors was prevented by o-phenanthroline, an inhibitor of PL-C. A similar effect on membrane-bound receptors was observed when lipids were extracted with ethanol-diethylether. On the other hand, treatment of water-soluble receptors with PL-C or delipidation of LFF with Amberlit IRA 400 had no effect on [125I]hCG specific binding. These data suggest that phospholipids play an important role in the accessibility of membrane-bound receptors but are not involved in direct interaction of gonadotropin with binding sites.
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PMID:Effect of phospholipase C induced hydrolysis of phospholipids on membrane-bound and water-soluble LH/hCG receptors in porcine corpora lutea. 162

Human preimplantation embryos and endometrium secrete platelet-activating factor (PAF). The mechanism of phosphatidylcholine (PC) degradation stimulated by PAF was investigated in endometrial explants prelabeled with [methyl-3H]choline or preincubated with [3H]butan-1-ol. Analysis of the water-soluble metabolites of PAF-induced PC hydrolysis in secretory endometrium demonstrated that the stimulated generation of [3H]choline ([3H]Cho) precedes that of [3H]choline phosphate ([3H]ChoP) and [3H]glycerophosphocholine ([3H]GPC). Within 30 sec there was a rapid rise in PAF-induced [3H]Cho generation and by 2 min this had increased to 59.9% +/- 10.6% (p less than 0.02), with no effect upon [3H]ChoP and [3H]GPC during this period. Both [3H]GPC and [3H]ChoP, however, were increased at a later time point. The slower [3H]ChoP generation may suggest that PC-specific phospholipase C activation as well as delayed [3H]GPC rise may be due to PC-specific phospholipase A2 and lysophospholipase activation. Phospholipase D activity was confirmed by the incorporation of high-specific-activity [3H]butan-1-ol into [3H]phosphatidylbutanol ([3H]PBut). The rapid generation of [3H]PBut, which paralleled the rise in intracellular [3H]Cho, strongly suggests that PC breakdown is catalyzed by the phospholipase D pathway. It is proposed that PAF induces PC hydrolysis as a consequence of an early phospholipase D-catalyzed breakdown of PC in human secretory endometrium. This may be an alternative source for prostaglandin synthesis and an important pathway essential for long-term activation of local cellular events at the time of implantation.
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PMID:Platelet-activating factor mediates phosphatidylcholine hydrolysis by phospholipase D in human endometrium. 163 48

Amastigotes of Leishmania major were isolated from infected mice and radiolabeled for 2 h with [3H]galactose. An acidic [3H]glycoconjugate was extracted from a dilipidated residue fraction with the solvent water/ethanol/diethylether/pyridine/NH4OH (15:15:5:1:0.017). The radioactivity labeled glycoconjugate was found to possess the following characteristics that were similar to the lipophosphoglycan extractable from promastigotes: (i) migrated as a broad band upon electrophoresis on SDS polyacrylamide gels; (ii) deaminated with nitrous acid; and (iii) hydrolyzed with phosphatidylinositol-specific phospholipase C. Furthermore, analysis of the aqueous soluble material released by the latter enzyme revealed a negatively-charged [3H]polysaccharide intermediate in size compared to the analogous portions of LPG isolated from non-infective and metacyclic promastigotes. Most importantly, the [3H]polysaccharide was found to contain phosphate and was susceptible to mild acid hydrolysis, establishing that the intact molecule is a lipophosphoglycan. A structural difference, however, was found in the major, mild acid-generated fragment of the amastigote phosphoglycan, which was larger in size and not as anionic as the analogous fragment from the promastigote phosphoglycans. These results indicate that the amastigotes do express a lipophosphoglycan, but that it is structurally distinct from its promastigote counterparts.
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PMID:Expression of a stage-specific lipophosphoglycan in Leishmania major amastigotes. 164 60

Tumor necrosis factor (TNF) is a proinflammatory polypeptide that is able to induce a great diversity of cellular responses via modulating the expression of a number of different genes. One major pathway by which TNF receptors communicate signals from the membrane to the cell nucleus involves protein kinase C (PKC). In the present study, we have addressed the molecular mechanism of TNF-induced PKC activation. To this, membrane lipids of the human histiocytic cell line U937 were labeled by incubation with various radioactive precursors, and TNF-induced changes in phospholipid, neutral lipid, and water-soluble metabolites were analyzed by thin layer chromatography. TNF treatment of U937 cells resulted in a rapid and transient increase of 1'2'diacylglycerol (DAG), a well-known activator of PKC. The increase in DAG was detectable as early as 15 s after TNF treatment and peaked at 60 s. DAG increments were most pronounced (approximately 360% of basal levels) when cells were preincubated with [14C]lysophosphatidylcholine, which was predominantly incorporated into the phosphatidylcholine (PC) pool of the plasma-membranes. Further extensive examination of changes in metabolically labeled phospholipids indicated that TNF-stimulated hydrolysis of PC is accompanied by the generation of phosphorylcholine and DAG. These results suggest the operation of a PC-specific phospholipase C. Since no changes in phosphatidic acid (PA) and choline were observed and the production of DAG by TNF could not be blocked by either propranolol or ethanol, a combined activation of phospholipase D and PA-phosphohydrolase in DAG production appears unlikely. TNF-stimulated DAG production as well as PKC activation could be blocked by the phospholipase inhibitor p-bromophenacylbromide (BPB). Since BPB did not inactivate PKC directly, these findings underscore that TNF activates PKC via formation of DAG. TNF stimulation of DAG production could be inhibited by preincubation of cells with a monoclonal anti-TNF receptor (p55-60) antibody, indicating that activation of a PC-specific phospholipase C is a TNF receptor-mediated event.
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PMID:Tumor necrosis factor induces rapid production of 1'2'diacylglycerol by a phosphatidylcholine-specific phospholipase C. 165 88

1. Phosphatidylinositol 4-phosphate (PtdIns4P) is degraded by isolated membranes from Xenopus laevis oocytes. 2. Incubation of [4-32P]PtdIns4P with membranes yields only radioactive inorganic phosphate, indicating the presence of a phosphomonoesterase. 3. Membranes hydrolyze Ptd[2-3H]Ins4P to produce mainly Ptd[2-3H]Ins in the lipid phase. In this incubation [3H]inositol and inositol monophosphate appear in the water phase. 4. Membrane incubations of Ptd[2-3H]Ins4P carried out in the presence of excess non-radioactive Ins(1,4)P2 allows the trapping of small amounts of [3H]Ins(1,4)P2. These results demonstrate the presence of a phospholipase C. 5. Testing several phosphorylated analogs, it is determined that fructose 1,6-bisphosphate and alpha-glycerophosphate are potent inhibitors of the oocyte PtdIns4P phosphomonoesterase.
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PMID:The hydrolysis of phosphatidylinositol 4-phosphate in membranes of Xenopus laevis oocytes: characteristics of a phosphomonoesterase. 166 8


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