Disease relevance of phosphatidic acids

• Secretion under these conditions is not accompanied by PA formation and is resistant both to depletion of Ca2+ from internal stores and to pertussis toxin (PtX) treatment [1].
• Pharmacological inhibition of synthesis of selected PA species may therefore provide a therapeutic approach to suppression of HIV replication [2].
• We have investigated whether the activity of the N-ethylmaleimide-sensitive ("metabolic") form of phosphatidate phosphohydrolase is increased in patients with alcoholic liver disease and whether any increased activity correlates with the severity of steatosis [3].
• The activity of the metabolic form of hepatic phosphatidate phosphohydrolase correlates with the severity of alcoholic fatty liver in human beings [3].
• DGPP phosphatases (DGPP phosphohydrolase) from Saccharomyces cerevisiae and Escherichia coli catalyze the dephosphorylation of DGPP to yield phosphatidate (PA) and then catalyze the dephosphorylation of PA to yield diacylglycerol [4].

Psychiatry related information on phosphatidic acids

• 1. The effects of dietary modification, including starvation, and of corticotropin injection on the activities of acyl-CoA synthetase, glycerol phosphate acyltransferase, dihydroxyacetone phosphate acyltransferase, phosphatidate phosphohydrolase, diacylglycerol acyltransferase and lipoprotein lipase were measured in adipose tissue [5].
• Phosphatidate, phosphatidylinositol, diacylglycerols, and free fatty acids in the brain following electroshock, anoxia, or ischemia [6].

High impact information on phosphatidic acids

• Cell stimulation causes diacylglycerol kinase (DGK) to convert the second messenger diacylglycerol into phosphatidate, thus initiating the resynthesis of phosphatidylinositols and attenuating protein kinase C activity [7].
• Following recent reports on the interactions of Ca2+ with phosphatidic acid in membranes and artificial systems, we investigated the hypothesis that phosphatidate accumulation mediates the action of cholinergic and other stimuli on Ca2+ influx [8].
• This alteration in phosphatidate metabolism does not seem to result from an increase in intracellular Ca2+ or depolarisation of the cell membrane [8].
• These results support the contention that cholinergic-induced changes in membrane Ca2+ permeability in smooth muscle could be mediated by phosphatidate accumulation [8].
• On the other hand, late DAG, derived from phosphatidic acid (PA) via PLD, may activate Ca(2+)-independent novel PKC isoforms (nPKC) [9].

Chemical compound and disease context of phosphatidic acids

• CT-2576 suppressed both PA generation induced by Tat and HIV long terminal repeat-directed gene expression in response to Tat or TNF-alpha at a posttranscriptional step [2].
• We have previously demonstrated that if C62B glioma cells are prelabeled with [1-14C]arachidonate, cholinergic stimulation results in liberation of radioactive arachidonate and accumulation of radioactive phosphatidate [10].
• Surprisingly, phosphatidic acid (PA), which did not induce increases in [Ca2+]i, p125FAK activation or activation of MAP kinases, did induce proliferation of ovarian cancer cells, albeit at higher concentrations that LPA [11].
• These data indicate that the development of fatty liver as an effect of 3-tetradecylpropionic acid is probably due to accelerated triglyceride biosynthesis, which is mediated by an increase in the availability of fatty acid along with stimulation of phosphatidate phosphohydrolase [12].
• Additional findings included elevated levels of PC for glioblastoma multiforme relative to neurofibroma, and neurilemmoma was differentiated from neurofibroma with elevated levels of PA and depressed levels of PI [13].

Biological context of phosphatidic acids

• Phagocytosis of either Erdman or H37Ra M. tuberculosis in the presence of autologous non-immune serum was associated with a 2.5-3-fold increase in phosphatidic acid (PA) [14].
• Phosphatidate (PA) is a central metabolite of lipid metabolism and a signaling molecule in many eukaryotes, including plants [15].
• Cellular activation in lymphoid cells is associated with augmented accumulation of certain phosphatidic acid (PA) species derived from the hydrolysis of glycan phosphatidylinositol (GPI) [2].
• Phosphatidate-dependent phosphorylation of a 30-kDa protein in the soluble fraction from heart was also observed [16].
• To test this hypothesis, we examined the effect of tat gene expression on the production of cellular PA species, as the Tat protein is essential for HIV expression and has been implicated in activating the expression of multiple host cellular genes [2].

Anatomical context of phosphatidic acids

• Furthermore, submicromolar concentrations of phosphatidate rapidly produce contractions of isolated smooth muscle cells [8].
• In eukaryotic cells, PAP activity has a central role in the synthesis of phospholipids and triacylglycerol through its product diacylglycerol, and it also generates and/or degrades lipid-signaling molecules that are related to phosphatidate [17].
• Histamine release induced by the introduction of a nonhydrolyzable analogue of GTP, GTP-gamma-S, into ATP-permeabilized mast cells, is associated with phosphoinositide breakdown, as evidenced by the production of phosphatidic acid (PA) in a neomycin-sensitive process [1].
• We propose that activation of PLD and the subsequent production of PA are key early events for the formation of coatomer-coated vesicles [18].
• Formation of coated vesicles was sensitive to ethanol at concentrations that inhibit the production of phosphatidic acid (PA) by PLD [18].

Associations of phosphatidic acids with other chemical compounds

• An increased turnover of phosphatidate and phosphatidyl inositol has been found in many tissues where hormones or neurotransmitters are postulated to raise Ca2+ influx, for example in smooth muscle [8].
• Lysophosphatidyl acyltransferase (LPAT) is a pivotal enzyme controlling the metabolic flow of lysophosphatidic acid into different phosphatidic acids in diverse tissues [19].
• These exogenous phospholipases have a preference for phosphatidylcholine with long polyunsaturated alkyl chains as substrates and, when added to permeabilized mast cells, produce multiple species of mono- and polyunsaturated diacylglycerols, phosphatidic acids, and lysophosphatidylcholines, respectively [20].
• Collectively, these data show that IL-8 stimulates the metabolism of choline-containing phosphoglycerides in human PMN and support a role for PA in the signaling mechanisms used by IL-8 to stimulate PMN function [21].
• Propranolol, an inhibitor of phosphatidate phosphohydrolase, caused a dose-dependent inhibition of both H2O2 and lactoferrin release, with maximal inhibition at 50-100 microM [22].

Gene context of phosphatidic acids

• Mutation of the TGD1 chloroplast envelope protein affects phosphatidate metabolism in Arabidopsis [15].
• Butan-1-ol, which acts as an acceptor of phosphatidate generated by the PLD pathway, blocked LPA-mediated transactivation of PDGF-R beta [23].
• The DPP1-encoded diacylglycerol pyrophosphate (DGPP) phosphatase enzyme accounts for half of the Mg2+-independent phosphatidate (PA) phosphatase activity in Saccharomyces cerevisiae [24].
• In comparison, ARF1 activates PLD, producing PA, which is a known activator of phosphatidylinositol-4-phosphate 5 kinase, the enzyme responsible for PIP2 synthesis [25].
• Because primary alcohols suppress the formation of the signaling lipid phosphatidic acid (PA) by phospholipase D (PLD), this observation prompted us to investigate whether PLD plays a role in the L1-mediated neurite outgrowth in CGNs [26].

Analytical, diagnostic and therapeutic context of phosphatidic acids

• Mass spectra of the respective phosphatidic acids were obtained by fast atom bombardment-mass spectrometry as described above [27].
• The effects of calcium on the mixing of synthetic diacylphosphatidylcholines (PC's) and diacylphosphatidylethanolamines (PE's) with the corresponding phosphatidic acids (PA's) have been examined by high-sensitivity differential scanning calorimetry and by measurements of the fluorescence of labeled PA or PC species in PA-PC bilayers [28].
• 5. The soluble phosphatidate phosphohydrolase activity tended to increase during perfusions of isolated rat livers without added substrates, and neither ethanol nor glycerol produced additional effects [29].
• After intravenous injection, these tracers were metabolized rapidly in the rat brain cortex to phosphatidic acids, phosphatidylinositols and phosphatidylinositol phosphates [30].
• The second step in stimulated phosphatidylinositol turnover, phosphorylation of diacylglycerol to phosphatidate was not affected by denervation [31].

References