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PubMed1991

Stimulation and inhibition of the activity of rat liver cytosolic phosphatidate phosphohydrolase by various phospholipids.

The influence of phospholipids on the activity of the soluble phosphatidate phosphohydrolase from rat liver was studied. Phosphatidylethanolamine stimulated the enzyme activity whereas phosphatidylglycerol, phosphatidylserine, and phosphatidylinositol were inhibitory. At a phospholipid concentration of 0.7 mg/ml, phosphatidylglycerol inhibited phosphatidate phosphohydrolase activity by 75%, while the enzyme activity was stimulated twofold in the presence of phosphatidylethanolamine. Both lysophosphatidylglycerol and lysophosphatidylethanolamine inhibited phosphatidate phosphohydrolase activity as did octylglucoside, sodium cholate, and Tween 20. The finding that phospholipids influence hepatic phosphatidate phosphohydrolase activity indicates that changes in the lipid environment may modulate the enzyme activity.

Animals↗
PubMedDate not supplied

Inhibition of phosphatidylserine synthesis by phosphatidic acid in the Jurkat T cell line: role of calcium ions released from intracellular stores.

Phosphatidic acid exogenously added to Jurkat T-cells, provokes a marked inhibition of phosphatidylserine (PS) synthesis. Comparison of the efficiency of synthetic phosphatidic acids, differing in their fatty acid content, to induce inhibition of PS-synthesis have shown that short chain saturated and long chain unsaturated fatty acid-containing phosphatidic acids were the best inhibitors. Treatment of Jurkat cells with phosphatidic acid, induced a mobilization of calcium ions arising exclusively from intracellular stores, suggesting that Ca2+ from intracellular compartments might play a key role in the inhibition of PS synthesis. In activated cells, the use of R59022, a diacylglycerolkinase inhibitor, suggests that PA and probably calcium ions released by PA are the messengers responsible for the inhibition of PS synthesis in Jurkat T cells.

Antibodies, Monoclonal↗
PubMed1990

Agonist-induced production of 1,2-diacylglycerol and phosphatidic acid in intact resistance arteries. Evidence that accumulation of diacylglycerol is not a prerequisite for contraction.

The production of total amounts of 1,2-diacylglycerol as well as those specifically derived from inositol lipid hydrolysis was studied in intact rat resistance arteries stimulated with either noradrenaline, vasopressin, or angiotensin II at 20 s when the onset of contraction would be nearing its maximum, and at 5 min during the sustained phase of contraction. Total amounts of 1,2-diacylglycerol were not altered by any agonist at 20 s, or at 5 min. However, arachidonate-containing species of 1,2-diacylglycerol were differentially influenced being increased at 5 min by noradrenaline, and decreased at 20 s and 5 min by vasopressin. Only angiotensin II produced substantial increases in this class of 1,2-diacylglycerol at both time points. In order to investigate the fate of this second messenger total and inositol lipid derived phosphatidic acids were then measured at both 20 s and 5 min. Noradrenaline induced a rise in both total and arachidonate-containing phosphatidic acid at both times as did vasopressin. Only small increases were induced by angiotensin II at 20 s. These data demonstrate that the accumulation of 1,2-diacylglycerol generated from inositol lipid breakdown is only observed with activation by angiotensin II. Other agonists produced phosphatidic acids with time and the rate of generation of these lipids is agonist-specific. Thus phosphatidic acid may play a more prominent role during the sustained phase of contraction than previously anticipated.

Angiotensin II↗
PubMed1985

Phosphatidate and monooleylphosphatidate inhibition of fibroblast adenylate cyclase is mediated by the inhibitory coupling protein, Ni.

It has previously been shown that monooleylphosphatidate (MOPA) and phosphatidate inhibit cAMP accumulation in VA13 and WI-38 fibroblasts. In this study we investigated whether this inhibition might be due to a decrease in adenylate cyclase activity. Our results showed that both MOPA and phosphatidate inhibit prostaglandin E1-stimulated adenylate cyclase in WI-38 membranes in a concentration-dependent manner with half-maximal inhibitions at 0.1 and 0.5 microM, respectively, and maximal inhibitions of 35-55%. A 5 microM concentration of structurally similar lipids caused no significant inhibition. The inhibitory effects of MOPA and phosphatidate on adenylate cyclase were GTP dependent, greater at low concentrations of Mg2+, eliminated following treatment of cells with islet-activating protein, nonadditive with carbachol, and noncompetitive with prostaglandin E1. Collectively these data suggested that MOPA and phosphatidate inhibitions of cAMP accumulation were due at least in part to an Ni-mediated inhibition of adenylate cyclase. Furthermore, the inhibitions showed the same characteristics normally associated with hormonal inhibition of this enzyme.

Adenosine Diphosphate Ribose↗
PubMed1984

Partial purification and properties of phosphatidate phosphatase in Saccharomyces cerevisiae.

Using an aqueous dispersion of [32P]phosphatidate as substrate we detected phosphatidate phosphatase (EC 3.1.3.4) activity in a cell-free extract of the yeast, Saccharomyces cerevisiae. The activity was found in both the membrane and the soluble fractions. The enzyme was purified from the soluble fraction about 600-fold. The purification procedure involved (NH4)2SO4 fractionation, poly(ethylene glycol) 6000 fractionation and column chromatography on DEAE-Sepharose, Sephadex G-100 and Blue-Sepharose. The purified enzyme almost absolutely required Mg2+ for activity. The molecular weight of the enzyme was estimated by analytical gel filtration on Sephadex G-100 to be approx. 75000. The enzyme was highly specific for phosphatidate. The apparent Km for phosphatidate was approx. 0.05 mM. The optimum pH was between 7.0 and 8.0.

Hydrogen-Ion Concentration↗
PubMed1982

Massive accumulation of phosphatidic acid in conditionally lethal CDP-diglyceride synthetase mutants and cytidine auxotrophs of Escherichia coli.

Escherichia coli mutants partially defective in CTP: phosphatidic acid cytidylyltransferase (CDP-diglyceride synthetase) are more resistant to the antibiotic erythromycin than are isogenic wild type strains. When 100 micrograms/ml erythromycin is added to nutrient agar plates, it is possible to obtain a 30-fold enrichment for cds mutants from a mutagen-treated stock, as judged by colony autoradiography (Ganong, B. R., Leonard, J. M., and Raetz, C. R. H. (1980) J. Biol. Chem. 255, 1623-1629). Using this approach, we have isolated 38 new cds mutants, nine of which are unable to grow at a culture pH greater than 8. A typical conditionally lethal mutant like GN80 contains a 3 to 5% phosphatidic acid below pH 7. Above pH 8, GN80 accumulates phosphatidic acid to about 30% of the total membrane lipid, while the de novo syntheses of phosphatidylethanolamine and phosphatidylglycerol are abruptly inhibited by over 10-fold. GN80 loses viability after 60 min at pH 8.5, and the liponucleotide pool of GN80 is about one-seventh that of an isogenic wild type, GN85, under these conditions. The pH optimum of the residual CDP-diglyceride synthetase present in extracts of GN80 is 0.5 pH units lower than normal. Twenty-one of 26 spontaneous pH-resistant revertants of GN80 concomitantly regain parental levels of the enzyme. Our results constitute definitive physiological proof that CDP-diglyceride is an obligatory precursor for over 90% of the phosphatidylethanolamine and phosphatidylglycerol in E. coli. Independent evidence for this is provided by the observation that cytidine auxotrophs, which are defective in the conversion of UTP to CTP, also accumulate very high levels of phosphatidic acid after 1 h of cytidine starvation.

Cytidine↗
PubMed1982

Stimulus-secretion coupling in the human neutrophil: the role of phosphatidic acid and oxidized fatty acids in the translocation of calcium.

Neutrophils, stimulated via their surface receptors by ligands such as f-Met-Leu-Phe or immune complexes, release membrane calcium from intracellular stores and accumulate calcium from the extracellular medium. Both mechanisms provide for a rise in the intracellular concentration of free calcium which appears to be required for later responses of the cell: release of lysosomal enzymes and the generation of superoxide anion as neutrophils undergo an aggregation response. Exogenous ionophores, such as A23187 and PGBx, which move calcium bidirectionally across lipid bilayers, bypass the ligand-receptor step, thereby providing the necessary rise in intracellular calcium. In the course of the remodeling of membrane lipids--within 5 sec after their exposure to a stimulus--neutrophils generate phosphatidic acid, at least in part at the expense of phosphatidyl inositol. Because phosphatidic acid is the only phospholipid whose action in model membranes mimics the action of exogenous ionophores (as it is formed early enough and in sufficient quantities to account for uptake of extracellular calcium), we propose phosphatidic acid as a promising candidate for the role of endogenous ionophore. This ionophoretic action may serve to amplify signals launched by primary changes at the plasma membrane from whence calcium is mobilized during stimulus-secretion coupling. The release of oxidation products of arachidonic acid, be it via the cyclo-oxygenase or lipoxygenase pathway, is a concomitant of neutrophil activation. Indeed, the pathways by which oxidative products of arachidonate are formed may also be influenced by stimulus-specific changes in membrane phospholipids, not the least interesting of which is the generation of phosphatidic acid.

Arachidonate Lipoxygenases↗
PubMed1983

Shape change induced in human platelets by platelet-activating factor. Correlation with the formation of phosphatidic acid and phosphorylation of a 40,000-dalton protein.

Washed human platelets that have been separated from plasma in the presence of prostacyclin are activated by the addition of platelet activating factor (PAF). Activation (shape change, serotonin release, and aggregation) correlates closely with the formation of phosphatidic acid and the phosphorylation of a 40,000-dalton protein. Platelet shape change, formation of phosphatidic acid, and protein phosphorylation precede aggregation and are induced at lower concentrations of PAF than those required to induce release of serotonin and platelet aggregation. Platelet shape change, formation of phosphatidic acid, and protein phosphorylation induced by PAF are not affected by trifluoperazine or indomethacin. This indicates that these responses are independent of the liberation of arachidonic acid from platelet phospholipids and the metabolism of arachidonic acid via cyclooxygenase and lipoxygenase. These responses are, however, inhibited by prostacyclin. Platelet shape change is the first measurable physiologic response to platelet agonists and may be associated with the stimulation of phospholipase C, inducing formation of 1,2-diacylglycerol and its phosphorylated product, phosphatidic acid. Transient formation of 1,2-diacylglycerol may also induce the specific activation of the protein kinase C that phosphorylates a 40,000-dalton protein.

Blood Platelets↗
PubMed1984

Phospholipase A1 acting on phosphatidic acid in porcine platelet membranes.

1-[14C]Palmitoyl-2-[3H]arachidonoyl-sn-glycerol 3-phosphate was hydrolyzed to form [14C]palmitic acid and 2-[3H]arachidonoyl-glycerophosphate by porcine platelet membranes. This phospholipase A1 activity was relatively specific for phosphatidic acid; the addition of several other phospholipids in equimolar amounts did not have a significant effect on the hydrolysis of radiolabeled phosphatidic acid, and the specific activity for phosphatidic acid hydrolysis was 20-fold higher than that of the hydrolysis of phosphatidylcholine, phosphatidylethanolamine, or phosphatidylinositol under the conditions used. This phospholipase A1 acting on phosphatidic acid has properties different from those reported for other phospholipases and lipases present in platelets.

Animals↗
PubMed1993

Low concentration of Triton X-100 inhibits diacylglycerol acyltransferase without measurable effect on phosphatidate phosphohydrolase in the human primordial placenta.

Agents causing accumulation of endogenous diacylglycerols (DAG) may be helpful in studies on the intracellular regulatory effects and on the mechanisms of attenuation of this putative second messenger. In a previous study (Tóth et al., BBA 921 (1987) 417-425) we have shown a marked stimulatory effect of low micellar concentration (0.05%, v/v) of Triton X-100 on the labelling of phosphatidic acid with (32P)phosphate in minced human primordial placenta. The present results demonstrate that 0.05% Triton X-100 inhibits nearly completely the conversion of (3H)diacylglycerols into (3H)triacylglycerols in placenta fragments incubated with (3H)glucose. However, this concentration of the detergent does not have any effect on the appearance of label in the sum of acylglycerols (comprising mono-, di- and triacylglycerols) and phosphatidylcholine, indicating a lack of effect on phosphatidate phosphohydrolase. The about 5-fold elevation of (3H)diacylglycerols was attended by an approximately 3-fold rise in (3H)phosphatidic acid and a 1.3-fold increase in the labelling of phosphatidylcholine. These findings provide supportive evidence that 1,2-DAG was formed due to inhibition of DAG-acyltransferase and suggest that some of the DAG was transformed into phosphatidic acid by diacylglycerol-kinase.

Acyltransferases↗
PubMed1975

Partial purification and properties of microsomal phosphatidate phosphohydrolase from rat liver.

Microsomal phosphatidate phosphohydrolase (phosphatidate phosphatase EC 3.1.3.4) was solubilized and fractionated to yield at least two distinct enzymatically active fractions. One, denoted FA, was non-specific, had a relatively high Km for phosphatidic acid and was insensitive to inhibition by diacylglycerol. The second fraction, FB, was specific for phosphatidates, had a low Km, and was inhibited, non-competitively, by diacylglycerol. FA exhibited a sigmoid substrate-activity curve. The isolated FB aggregated to particles of about 10(6) in the absence of salts and could be dissociated by the addition of monovalent cations at ionic strength 0.4-0.6 to about 2-10(5) daltons and thereby doubled its activity. Dissociation was time- and temperature-dependent. F- was inhibitory. Divalent ions were not required for the activity of FA or FB and inhibited at concentrations exceeding 1 mM.

Animals↗
PubMed1969

Phosphatidate biosynthesis in mitochondrial subfractions of rat liver.

1. After conventional fractionation of rat liver homogenates in 0.88m-sucrose the mitochondrial fraction was subjected to short-term water lysis followed by separation of the resulting membrane preparations. 2. Phosphatidate formation was measured in all subcellular fractions and subfractions and was compared with the distribution of succinate dehydrogenase, monoamine oxidase, rotenone-insensitive NADH cytochrome c reductase, arylsulphatase, urate oxidase, arylesterase and glucose 6-phosphatase. 3. The results obtained indicated that mitochondria were capable of synthesizing phosphatidate, though this activity was only about one-third of the total homogenate activity. 4. Mitochondrial phosphatidate formation was located predominantly in the outer mitochondrial membrane. Although this membrane preparation was found to be significantly contaminated by the microsomal fraction, this contamination was estimated to account for not more than about 20% of the total phosphatidate formation observed in preparations of outer mitochondrial membrane.

Animals↗
PubMed1972

Resolution and reconstitution of the phosphatidate-synthesizing system of rat-liver microsomes.

The phosphatidate-synthesizing system of rat-liver microsomes was resolved into two component enzymes, glycerolphosphate acyltransferase and 1-acylglycerolphosphate acyltransferase. The resolution is effected by sucrose density gradient centrifugation in the presence of a nonionic detergent, Triton X-100. Combination of both enzymes results in reconstitution of the phosphatidate-synthesizing system. These results establish that two distinct enzymes, glycerolphosphate acyltransferase and 1-acylglycerolphosphate acyltransferase, are required for synthesis of phosphatidic acid from sn-glycerol 3-phosphate.Furthermore, the 1-acylglycerolphosphate acyltransferase preparation efficiently uses unsaturated (or saturated) fatty acyl-CoA as acyl donor. Our previous studies showed that the glycerolphosphate acyltransferase preparation catalyzes formation of 1-acylglycerol 3-phosphate, using preferentially saturated fatty acyl-CoA as acyl donor. These findings indicate that the reconstituted system is capable of yielding phosphatidic acid with an asymmetric fatty acid distribution.

Acetyltransferases↗
PubMed1975

[A clinical experimental study on the therapeutically effective component of retinal phosphatides (author's transl)].

In the present study it was demonstrated that neither the relation of the single phosphatide components nor the organ which serves as the source of the phosphatides have any importance on the therapeutic effect on the retina. The therapeutic effect of the phosphatide depends on their content of C 22:6. The phosphatide complex from livers of pigs, feeded with fish, has a particularly high content C 22:6. Its therapeutic effect and its production offers great technical and economical advantages.

Animals↗
PubMed1970

Reactions of activated factor X-phosphatide mixtures in vitro and in vivo.

The composition, surface properties, and capacity of lipid particles to bind activated factor X can be correlated both with the influence of various phosphatide combinations on activated factor X activity in vitro and on the intensity and duration of the thrombogenic stimulus as measured by a standard bioassay for thrombus formation. The measurable activity of activated factor X in vitro increased as a linear function of lipid concentration from 0 to 40 micro moles/liter. The effectiveness of the lipids examined was in the following decreasing order: phosphatidyl serine-phosphatidylcholine mixture, "cephalin", and phosphatidyl serine alone. An increase in the duration of hypercoagulability with increasing lipid concentration was also observed, but, with regard to the three lipid fractions tested, the in vivo system appeared to be more discriminatory than in vitro assays. Lipid mixtures containing phosphatidyl serine with either phosphatidylcholine, phosphatidyl ethanolamine, or cetyltrimethylammonium bromide markedly enhanced the in vitro activity of activated factor X. Phosphatidic acid-phosphatidylcholine mixtures had a similar but smaller effect, and phosphatidyl ethanolamine-phosphatidylcholine mixtures were inert. The duration of the hypercoagulability was similarly related to the composition of the phosphatide infused. In mixtures containing phosphatidyl serine, the surface charge density of the lipid particles and the binding of the activated factor X activity to lipid showed some correlations with the in vitro activated factor X assay and with the intensity and duration of the thrombogenic stimulus. These data suggest that the catalytic effect of phosphatides on prothrombin activation and their role in the retardation of in vivo compensatory mechanisms directed against circulating activated factor X, are dependent on the affinity of activated factor X for the lipid surface.

Animals↗
PubMed1966

Lipid monolayers: action of phospholipase A of Crotalus atrox and Naja naja venoms on phosphatidyl choline and phosphatidal choline.

The activity of phospholipase A on phosphatidyl choline and phosphatidal choline spread as monolayers on phosphate buffers containing snake venom (Crotalus atrox or Naja naja) was studied by measuring the fall of surface potential as a function of time, pH, film pressure, temperature, and concentrations of phosphate and venom. At 25 degrees C, pH 7.0, and 0.2 micrograms of venom per ml, optimal activity was observed with both venoms on both substrates at 12 dynes/cm film pressure on 0.04 m phosphate. Under these conditions, the pH optimum for C. atrox was broad (6.6-7.4) and that for N. naja was sharp (8.0) for the action on phosphatidyl choline, whereas both venoms had a sharp optimum at pH 8.0 in their action on phosphatidal choline. The optimal temperature with phosphatidyl choline was 27.5 degrees C for N. naja and 40 degrees C for C. atrox. In line with studies of phospholipase A activity in bulk phase in ether, phosphatidal choline was attacked much more slowly than phosphatidyl choline by C. atrox. Under conditions where both venoms had equal activity on phosphatidyl choline, C. atrox was only half as active as N. naja on phosphatidal choline. The studies suggest that the linkage of the hydrophobic chains in glycerophosphatides may affect their interaction with proteins.

Animals↗
PubMed1998

Identification of a novel human phosphatidic acid phosphatase type 2 isoform.

Two human isoforms of membrane associated phosphatidic acid phosphatase have been described (PAP-2a and -2b), and both enzymes have been shown to have broad substrate specificity and wide tissue distribution [Kai et al., J. Biol. Chem. 272 (1997) 24572-24578]. With this report we describe a third isoform, PAP-2c, that we found by searching the database of expressed sequence tags (dbEST) with PAP-2a and PAP-2b sequences. Key structural features described previously in PAP-2a and -2b, including the glycosylation site, putative transmembrane domains, and the proposed catalytic site, are conserved in the novel phosphatase. The kinetics of the three enzymes were compared using as substrates phosphatidic acid, lysophosphatidic acid, and N-oleoyl ethanolamine phosphatidic acid. Km values for each of the substrates, respectively, were (in microM) PAP-2a: 98, 170, 116; PAP-2b: 100, 110, 56; and PAP-2c: 150, 340, 138. Expression of PAP-2c mRNA is more restricted than the two previously described isoforms.

Amino Acid Sequence↗
PubMed1998

Diacylglycerol pyrophosphate: a novel metabolite in the Trypanosoma cruzi phosphatidic acid metabolism.

This work provides evidence that phosphatidic acid (PA) is metabolized to diacylglycerol pyrophosphate (DGPP) in Trypanosoma cruzi. Also the presence of the enzymatic activities involved in its regulation, phosphatidate kinase (PA-k) and phosphatidate phosphatase, is demonstrated. The increase of DGPP levels in T. cruzi epimastigotes or in its membrane fraction after exogenous PA addition or phospholipase (PLD) pre-treatment suggests that PA-k may be involved in the regulation of PA levels after its stimulation.

Animals↗