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 have reported that peroxisomal beta-oxidation has an anabolic function, supplying acetyl-CoA for biosyntheses of bile acids and phospholipids. Here we deal with its role in the biosynthesis of the subclasses of ethanolamine- and choline-containing phosphoglycerides (EPG, CPG, respectively). Rats were fed for 2 weeks on chow containing 0.25% clofibrate, which inhibits cholesterol and bile acid biosyntheses, but stimulates peroxisomal beta-oxidation. [1-14C]Lignoceric acid, which is exclusively degraded by peroxisomal beta-oxidation to acetyl-CoA, was intravenously injected, and 3 h later the rats were killed. The EPG-rich and CPG-rich fractions were prepared from the liver. When they were treated with phospholipase A2, the radioactivity was predominantly recovered in the 1-radyl group. The radioactivity in EPG was easily dissociated with HCl vapor, and the lipid containing radioactivity was found to be a fatty aldehyde mixture consisting of steary aldehyde (approx. 58%) palmityl aldehyde (approx. 40%) and oleyl aldehyde (approx. 2%). Thus, in the case of EPG, acetyl-CoA from peroxisomal beta-oxidation is incorporated mainly into the 1-alkenyl group of ethanolamine plasmalogen. The radioactivity in CPG, however, was found in fatty alcohol (formed from fatty acid), but not in alkylglycerol after reduction of the fraction with Vitride. Thus, in the case of CPG, acetyl-CoA from peroxisomal beta-oxidation is exclusively incorporated into the 1-acyl group of diacyl glycerophosphocholine, but not into the 1-alkyl group. The above results were supported by the results of phospholipase C treatment. The above data indicate that peroxisomal beta-oxidation plays a role in supplying acetyl-CoA for 1-alkenyl group of plasmalogen-type phospholipid, but this channel may open only to synthesis of EPG, and almost not to CPG.
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PMID:Incorporation of acetyl-CoA generated from peroxisomal beta-oxidation into ethanolamine plasmalogen of rat liver. 785 72

2-Iodohexadecanal (IHDA) has been identified as a major thyroid iodolipid which can be formed upon addition of iodine to the vinyl ether group of plasmalogens (Pereira et al., 1990). In order to test whether IHDA plays a role in the thyroid autoregulation by iodide, we have investigated its effects on the production of H2O2 by cultured dog thyroid cells. IHDA inhibited the formation of H2O2 in dog thyroid cells stimulated by carbamylcholine (CCHOL). In the presence of BSA, which potentiated its action, the effect of IHDA was maximal after 2 h and had an IC50 around 5 microM. The effect of IHDA was not decreased by methimazole, which abolished the inhibition by iodide. IHDA also inhibited the stimulatory effect of bradykinin, but had only a marginal effect on the production of H2O2 induced by ionomycin or phorbol 12-myristate 13-acetate (PMA). The accumulation of inositol phosphates in CCHOL-stimulated thyroid cells was decreased by IHDA. As evaluated by measurements of 51Cr release and [3H]thymidine incorporation into DNA, IHDA had no adverse effect on thyroid cell viability. Several analogs of IHDA, of which the synthesis is described, have been tested for their inhibitory activity. This allowed the identification of two major structural features required for the biological activity: the carbonyl group at C1 and an halogen atom at C2, with iodine conferring a greater activity than bromine, while chlorine and fluorine were inactive. In conclusion, IHDA inhibits the production of H2O2 in CCHOL-stimulated dog thyroid cells by decreasing the phospholipase C cascade activity. This effect involves both the aldehyde function and the iodine atom. These results suggest that IHDA might be the mediator of some of the regulatory actions of iodide on the thyroid gland.
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PMID:Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells. 792 69

Alternations of stomach mucose caused by ethanol are in direct correlation with its concentration. ADH in stomach mucose is an efficient barrier against ethanol system toxicity. It stimulates higher secretion of HC1, dilutes protective barrier of mucose and phospholipids in membranes. Inflammatory reaction also participates in the damage of stomach mucose, with a share of products of arachidonic metabolism and free radicals. After ethanol administration the pancreas blood circulation diminishes and resistance in microcirculation increases. This can cause necroses in periphery of lobules. Activated phospholipase C may result in hypersecretion of Ca2+ dependent proteinkinases. Ischemic changes participate in alcohol impairment of pancreas and increase its vulnerability to enzyme attract and free radical reactions. Ethanol excesses may result in diarrhoea, dyspepsia, malnutrition and cause morphologic alternations of intestinal mucose (erosion, hemorrhagia). Absorption of nutrients and vitamins is affected by inhibition of active transport or by decrease of enzyme activity. Ethanol increases mucose permeability, alteres intestinal motility and damages absorption of water and electrolytes. In chronic alcoholics lower villi and changes in bacterial flora are described. The following mechanism of ethanol caused liver injury are observed: acetaldehyde toxicity, change in NAD+/NADH ratio connected with acidosis, cytoskeletal impairment, inhibition of protein synthesis and their secretion, relative perivenular hypoxia, activation of fibrogenesis, increased formation of free radicals with lipid peroxidation and immunological reaction. In hepatocyte there are morphological changes (megamitochondria, etc.) and functional changes (inhibition of glycolysis, inhibition of Krebs cycle and beta oxidation of fatty acids). Ethanol intake activates leukocytes, trombocytes, endothelial and Kupffer cells and their mediators, which result in increase of collagen and proteoglycans synthesis furthermore in fibrotic changes in liver.
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PMID:[Ethanol metabolism and pathobiochemistry of organ damage--1992. III. Mechanisms of damage to the gastrointestinal tract and the liver by ethanol]. 799 16

Our work has evaluated the effects of certain lipid peroxidation products, i.e. 4-hydroxy-2,3-trans-nonenal (HNE), 4-hydroxy-2,3-trans-octenal (HOE), 2-trans-nonenal and nonanal, on phosphoinositide-specific phospholipase C (PL-C). The enzymatic activity has been determined in vitro by measuring the hydrolysis of labelled phosphatidylinositol-4,5-bisphosphate added to plasma membranes isolated from rat neutrophils. Concentrations of HNE between 10(-8) and 10(-6) M, and concentrations of HOE ranging from 10(-11) to 10(-8) M, were able to activate PL-C. Neither 2-trans-nonenal nor nonanal induced any change of PL-C activity. HNE, HOE and 2-nonenal, but not nonanal, have been shown to possess chemotactic properties towards rat neutrophils. The good correlation between the concentrations of HNE and HOE active on PL-C and those able to stimulate cell migration suggests that their chemotactic activity might be mediated by the activation of PL-C, as in the case of most chemoattractants. On the contrary, this mechanism of action cannot be applied to 2-nonenal, an aldehyde much more hydrophobic than HNE or HOE; its chemotactic activity might be the consequence of some perturbation of the lipidic environment of the cell membrane where it dissolves easily.
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PMID:Effect of 4-hydroxy-2,3-trans-nonenal and related aldehydes on phospholipase C activity of rat neutrophils. 807 89

4-Hydroxynonenal (HNE), a major lipid peroxidation product, displays several biological actions. Among them, the differentiation of human HL-60 cells and the stimulation of neutrophil oriented migration occur at concentrations which can be actually found in normal tissues and in body fluids. In spite of its chemotactic activity, HNE fails to increase neutrophil oxidative metabolism. The action of the aldehyde on cell migration appears to be mediated by a phosphoinositide specific phospholipase C. The acceleration of phosphatidylinositol turnover induced by 10 pM 4-hydroxyoctenal, another lipid peroxidation product, is prevented by the pretreatment of neutrophils with pertussis toxin. The mechanism of action of these 4-hydroxyalkenals appears to follow pathways common to other chemoattractants, but some differences can be found too. In particular HNE seems unable to stimulate phospholipase D activity. The action of 4-hydroxyalkenals and other lipid peroxidation products on transmembrane signalling systems and on phospholipid metabolism might regulate several cell functions, such as motility, proliferation and differentiation.
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PMID:Action of lipid peroxidation products on phosphoinositide specific phospholipase C. 826 43

We have isolated the core aldehydes (aldehydes still bound to parent molecules) of phosphatidylcholine (PC) and cholesteryl esters (CE) from copper-catalyzed peroxidation of human plasma low (LDL) and high (HDL) density lipoproteins. The aldehydes were isolated by extraction with acidified chloroform-methanol containing 2,4-dinitrophenylhydrazine. The 2,4-dinitrophenylhydrazone (DNPH) derivatives formed were resolved by reversed phase high performance liquid chromatography (HPLC) and identified by on-line quadrupole mass spectrometry (LC/MS). The major PC core aldehydes from oxidized LDL and HDL were identified as 1-palmitoyl-(1-stearoyl) 2-(9-oxononanoyl)-, 1-palmitoyl-(1-stearoyl) 2-(8-oxooctanoyl)-, and 1-palmitoyl-(1-stearoyl) 2-(5-oxovaleroyl)-sn-glycerols after phospholipase C digestion of the DNPH derivatives of the phospholipids. The major aldehydes from peroxidation of cholesteryl esters were the 9-oxononanoyl, 8-oxooctanoyl, and 5-oxovaleroyl esters of cholesterol and 7-ketocholesterol. The core aldehydes were estimated to account for a minimum of 1-2% of the consumed linoleate and arachidonate esters. A relatively smaller yield of the PC core aldehydes from LDL compared to HDL was attributed to the presence of greater amounts of phospholipases in LDL than in HDL. More comparable yields of PC core aldehydes were obtained in the presence of phenylmethylsulfonylfluoride, which inhibits phospholipases. We conclude that peroxidation of LDL and HDL results in formation of detectable amounts of cholesteryl and glycerophospholipid esters containing aldehyde functions. The yield of PC aldehydes varies with the activity of the platelet activating factor (PAF) acetyl hydrolase.
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PMID:Lipid ester-bound aldehydes among copper-catalyzed peroxidation products of human plasma lipoproteins. 855 76

Addition of micromolar concentrations of 4-hydroxynonenal (4-HNE), a reactive end-product of lipid peroxidation, to isolated rat hepatocytes was found to cause an early and transient increase in cytosolic Ca2+ concentration followed by a more pronounced and progressive elevation. Such a late effect of 4-HNE was prevented by chelation of extracellular Ca2+ with EGTA or by the addition of GdCl3, which is known to block the activity of store operated Ca2+ channels in the hepatocyte plasma membrane. Moreover, the preincubation of isolated hepatocytes with the phospholipase C inhibitor U73122 resulted in a complete inhibition of both the early increase of cytosolic Ca2+ and the subsequent Ca2+ inflow. When 4-HNE was added to the hepatocytes 5 min after the emptying of intracellular Ca2+ pools by thapsigargin, the aldehyde caused a further increase in the accumulation of Ca2+ which was prevented in the presence of GdCl3. Taken together these results indicate that in hepatocytes 4-HNE causes Ca2+ inflow across GdCl3-sensitive Ca2+ channels. The mechanism responsible for such an effect is triggered by the emptying of intracellular Ca2+ pools likely resulting from 4-HNE mediated stimulation of phospholypase C, but 4-HNE also appears to interfere with the channel protein(s) or with the mechanism(s) regulating capacitative Ca2+ inflow.
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PMID:4-Hydroxynonenal triggers Ca2+ influx in isolated rat hepatocytes. 857 89

Analogues of the P2 receptor antagonists pyridoxal-5'-phosphate and the 6-azophenyl-2',4'-disulfonate derivative (PPADS), in which the phosphate group was cyclized by esterification to a CH2OH group at the 4-position, were synthesized. The cyclic pyridoxine-alpha4, 5-monophosphate, compound 2 (MRS 2219), was found to be a selective potentiator of ATP-evoked responses at rat P2X1 receptors with an EC50 value of 5.9 +/- 1.8 microM, while the corresponding 6-azophenyl-2',5'-disulfonate derivative, compound 3 (MRS 2220), was a selective antagonist. The potency of compound 3 at the recombinant P2X1 receptor (IC50 10.2 +/- 2.6 microM) was lower than PPADS (IC50 98.5 +/- 5.5 nM) or iso-PPADS (IC50 42.5 +/- 17.5 nM), although unlike PPADS its effect was reversible with washout and surmountable. Compound 3 showed weak antagonistic activity at the rat P2X3 receptor (IC50 58.3 +/- 0.1 microM), while at recombinant rat P2X2 and P2X4 receptors no enhancing or antagonistic properties were evident. Compounds 2 and 3 were found to be inactive as either agonists or antagonists at the phospholipase C-coupled P2Y1 receptor of turkey erythrocytes, at recombinant human P2Y2 and P2Y4 receptors, and at recombinant rat P2Y6 receptors. Similarly, compounds 2 and 3 did not have measurable affinity at adenosine A1, A2A, or A3 receptors. The lack of an aldehyde group in these derivatives indicates that Schiff's base formation with the P2X1 receptor is not necessarily required for recognition of pyridoxal phosphate derivatives. Thus, compounds 2 and 3 are relatively selective pharmacological probes of P2X1 receptors, filling a long-standing need in the P2 receptor field, and are also important lead compounds for future studies.
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PMID:A pyridoxine cyclic phosphate and its 6-azoaryl derivative selectively potentiate and antagonize activation of P2X1 receptors. 963 52

The promyelocytic cell line HL-60 has been used as an in vitro model to study the mechanism of action of two chemotactic aldehydes, 2-nonenal and 4-hydroxynonenal. Increasing aldehyde concentrations have been added to undifferentiated and DMSO-differentiated cells incubated at 37 degrees C and their effect on phosphoinositide-specific phospholipase C has been analysed by using a specific inositol-1,4,5-tris-phosphate assay system. Concentrations of 2-nonenal between 10(-9) and 10(-7) M significantly increased the enzymatic-activity in DMSO-differentiated HL-60 cells, while 10(-9) and 10(-8) M concentrations were active in the undifferentiated cells. 4-Hydroxynonenal was able to activate phospholipase C both in undifferentiated and DMSO-differentiated cells at concentrations ranging from 10(-8) to 10(-6) M. The concentrations of both compounds active on phospholipase C displayed a good correspondence with those which had been reported to be chemotactic towards rat neutrophils. In the case of 4-hydroxynonenal, the present results confirm its ability to activate phospholipase C, which we had previously shown in isolated neutrophil plasma membranes. The comparison of the effects of 2-nonenal and 4-hydroxynonenal on chemotaxis and phospholipase C activation suggests a common mechanism of action for both aldehydes, for which the presence of the double bond seems to be required.
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PMID:Action of 2-nonenal and 4-hydroxynonenal on phosphoinositide-specific phosopholipase C in undifferentiated and DMSO-differentiated HL-60 cells. 1096 58

Novel analogues of the P2 receptor antagonist pyridoxal-5'-phosphate 6-azophenyl-2',5'-disulfonate (2) were synthesized and studied as antagonists in functional assays at recombinant rat P2X1, P2X2, and P2X3 receptors expressed in Xenopus oocytes (ion flux stimulation) and at turkey erythrocyte P2Y1 receptors (phospholipase C activation). Selected compounds were also evaluated as antagonists of ion flux and the opening of a large pore at the recombinant human P2X7 receptor. Modifications were made in the 4-aldehyde and 5'-phosphate groups of the pyridoxal moiety: i.e. a CH2OH group at the 4-position in pyridoxine was either condensed as a cyclic phosphate or phosphorylated separately to form a bisphosphate, which reduced potency at P2 receptors. 5-Methylphosphonate substitution, anticipated to increase stability to hydrolysis, preserved P2 receptor potency. At the 6-position, halo, carboxylate, sulfonate, and phosphonate variations made on the phenylazo ring modulated potency at P2 receptors. The p-carboxyphenylazo analogue, 4, of phosphate 2 displayed an IC50 value of 9 nM at recombinant P2X1 receptors and was 1300-, 16-, and > 10,000-fold selective for P2X1 versus P2X2, P2X3, and P2Y1 subtypes, respectively. The corresponding 5-methylphosphonate was equipotent at P2X1 receptors. The 5-methylphosphonate analogue containing a 6-[3,5-bis(methylphosphonate)]phenylazo moiety, 9, had IC50 values of 11 and 25 nM at recombinant P2X1 and P2X3 receptors, respectively. The analogue containing a phenylazo 4-phosphonate group, 11, was also very potent at both P2X1 and P2X3 receptors. However, the corresponding 2,5-disulfonate analogue, 10, was 28-fold selective for P2X1 versus P2X3 receptors. None of the analogues were more potent at P2X7 and P2Y1 receptors than 2, which acted in the micromolar range at these two subtypes.
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PMID:Structure-activity relationships of pyridoxal phosphate derivatives as potent and selective antagonists of P2X1 receptors. 1146 75


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