Disease relevance of [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice [1].
• Protection from endotoxic shock in mice by pharmacologic inhibition of phosphatidic acid [2].
• Myotonic dystrophy: calcium-dependent phosphatidic acid synthesis in erythrocytes [3].
• Recently it was reported that calcium-dependent phosphatidic acid synthesis in erythrocyte of patients with myotonic muscular dystrophy (MyD) is markedly impaired when compared to that in control subjects [3].
• AA labeled phospholipids similarly at both 4 degrees C and 37 degrees C. Analysis of the ratios of [(3)H] AA and [(14)C] glycerol incorporated into phosphatidic acid or other phospholipids in dual-labeled cells indicated that the deacylation/reacylation cycle was the major route of AA incorporation at hypothermia [4].

Psychiatry related information on [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• Furthermore, the simultaneous addition of phosphatidic acid and collagen shortened the latency period but had no effect on platelet aggregation [5].
• A defect of PI-cycle in the transformation from 1,2-diacylglycerol into phosphatidic acid was found in three patients, who were diagnosed as having Schizophrenic Disorders or Schizophreniform Disorder according to the DSM-III criteria [6].

High impact information on [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• Phospholipase D hydrolyzes phospholipids to produce phosphatidic acid and the respective head group [7].
• Unexpectedly, we find that the GTPgammaS-dependent activator of PI(4)P5Kalpha is the small G protein ADP-ribosylation factor (ARF) and that the activation strictly requires phosphatidic acid, the product of phospholipase D (PLD) [8].
• CDP-diacylglycerol synthase (CDS) is an enzyme required for the regeneration of the signalling molecule phosphatidylinositol-4,5-bisphosphate (PtdlnsP2) from phosphatidic acid [9].
• An early response to the tyrosine kinase activity of v-Src is an increase in phospholipase D (PLD) activity, which leads to the generation of biologically active lipid second messengers, including phosphatidic acid, lysophosphatidic acid and diacylglycerol [10].
• Failure of phosphatidic acid to translocate Ca2+ across phosphatidylcholine membranes [11].

Chemical compound and disease context of [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• The recombinant protein, which we expressed in Sf9 insect cells using the baculovirus system, hydrolyzed a fatty acyl residue at the sn-1 position of lysophosphatidylserine and phosphatidylserine, but did not appreciably hydrolyze phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, and triglyceride [12].
• Monocyte migration to phosphatidic acid and lysophosphatidic acid, but not to diacylglycerol, was inhibited in a concentration-dependent manner by Bordetella pertussis toxin, while cholera toxin was ineffective [13].
• Cholinergic stimulation of arachidonic acid and phosphatidic acid metabolism in C62B glioma cells [14].
• However, sphingosine 1-phosphate-induced phosphatidic acid accumulation was unaffected by pertussis toxin [15].
• Stimulation of phosphatidic acid of calcium influx and cyclic GMP synthesis in neuroblastoma cells [16].

Biological context of [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• Postulated roles of phosphatidic acid produced by phospholipase D action include the activation of Ca(2+)-independent isoforms of protein kinase C, the regulation of growth and the cytoskeleton in fibroblasts, and control of the respiratory burst in neutrophils [17].
• The hydrolysis of phosphatidylcholine by phospholipase D (PLD) results in the production of phosphatidic acid and choline [18].
• Resulting disruptions of intracellular signaling cascades through interference with the synthesis of phosphatidic acid, decreases in phosphorylation potential and lipid peroxidation are mechanisms by which solvent alcohols can affect the rate of cell proliferation and, consequently, cell number [19].
• It is not known how Gram-positive bacterial pathogens carry out glycerol-3-phosphate (G3P) acylation, which is the first step in the formation of phosphatidic acid, the key intermediate in membrane phospholipid synthesis [20].
• Phospholipase D, which hydrolyzes phospholipids (primarily phosphatidylcholine) to generate phosphatidic acid, has emerged as a critical component in cellular signal transduction [21].

Anatomical context of [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• Our evidence suggests that in neutrophils, PI breakdown and PA labelling are both consequences and not causes of a rise in intracellular Ca2+ [22].
• Both biochemical and genetic data indicate that regulation of the membrane content of phosphatidic acid, diacylglycerol and phosphoinositides is necessary for protein traffic from the Golgi complex [23].
• On the other hand, phosphatidic acid, the physiologic product of phospholipase D action on phospholipids, was found to mimic the effect of anti-Kp43 monoclonal antibody regarding tumor necrosis factor alpha (TNF-alpha) biosynthesis and secretion by NK cells [24].
• This study examines two calcium-dependent membrane processes that have been observed in erythrocytes from healthy individuals: calcium-stimulated phosphatidic acid accumulation and calcium-induced potassium leak [25].
• Phospholipase D-modified low density lipoprotein is taken up by macrophages at increased rate. A possible role for phosphatidic acid [26].

Associations of [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid with other chemical compounds

• Arachidonic acid and phosphatidic acid inactivate GAP, but no agents have been identified that stimulate GAP and thereby switch p21ras off [27].
• In cells labeled with L-lyso-3-PC 1-[1-14C]palmitoyl, PLD but not IL-4, increased the production of phosphatidic acid (PA) and phosphatidyl-ethanol when pretreated with ethanol [28].
• However, phosphatidic acid-induced TNF-alpha production was strongly inhibited by the presence of propranolol, an inhibitor of phosphatidic acid phosphohydrolase [24].
• Involvement of a phospholipase D in the mechanism of action of granulocyte-macrophage colony-stimulating factor (GM-CSF): priming of human neutrophils in vitro with GM-CSF is associated with accumulation of phosphatidic acid and diradylglycerol [29].
• The osmolyte hypothesis predicts diminished phosphoinositide-derived arachidonyl-diacylglycerol, while the redox hypothesis predicts increased total diacylglycerol and phosphatidic acid [30].

Gene context of [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• In addition, phosphatidic acid (containing arachidonic and stearic acid) was inhibitory for the catalytic fragment of NF1 protein, but did not inhibit the catalytic fragments of GAP or IRA2 proteins [31].
• These data suggest that PLD supports 'bypass Sec14p' by generating a phosphatidic acid pool that is somehow utilized in supporting yeast Golgi secretory function [32].
• Phospholipase D alpha 1-derived phosphatidic acid interacts with ABI1 phosphatase 2C and regulates abscisic acid signaling [33].
• Syntrophins are scaffold proteins that regulate the subcellular localization of diacylglycerol kinase zeta (DGK-zeta), an enzyme that phosphorylates the lipid second-messenger diacylglycerol to yield phosphatidic acid [34].
• When formation of phosphatidic acid was inhibited by overexpression of catalytically inactive PLD during etoposide treatment, expression of Egr-1 and PTEN and the apoptotic effect of etoposide were not inhibited [35].

Analytical, diagnostic and therapeutic context of [(2R)-2-pentadecanoyloxy-3-tridecanoyloxy-propoxy]phosphonic acid

• Bronchoalveolar lavage fluid was further analyzed for phospholipids and for phosphatidic acid phosphohydrolase, phospholipase A2, and phosphatidylinositol phosphodiesterase activities [36].
• The monoclonal IgM bound to ELISA microwells coated with a mixture of phosphatidic acid and gangliosides at serum dilutions of up to 1/100,000, but binding to phosphatidic acid alone was observed at dilutions of less than 1/100 only, and there was no binding to gangliosides alone [37].
• These products were identified as phosphatidic acid (PA), phosphatidylinositol 4-phosphate (DPI), and phosphatidylinositol 4,5-bisphosphate (TPI) based on their chromatographic mobilities on Silica Gel H and cellulose thin layer plates, and by analysis of their deacylation products by high pressure liquid chromatography [38].
• Electrical stimulation of the sciatic nerve of the anesthetized rat in vivo led to a time-dependent translocation of protein kinase C and a 2-fold increase in the concentrations of both diacylglycerol and phosphatidic acid [39].
• After treatment with 0.4 unit/ml of phospholipase D (20 min, 37 degrees C), the sarcolemmal content of phosphatidic acid rose from 0.9 +/- 0.2 to 8.9 +/- 0.4%; simultaneously, Na+-Ca2+ exchange activity increased 327 +/- 87% [40].

References