Disease relevance of phosphatidic acid

• IL-1 stimulation of a murine T cell (thymoma) line, EL-4, also caused stimulation of lyso-PA AT, resulting in PA formation [1].
• Pertussis toxin blocked the PA production [2].
• H148G induced neither the PA formation nor hemolysis [2].
• GTP and AIF4- significantly stimulated the late phosphatidic acid (PA) formation induced by Clostridium perfringens alpha-toxin in rabbit erythrocyte lysates [2].

High impact information on phosphatidic acid

• In propranolol pretreated cells, PMA but not IL-4 triggered the production of PA and lowered the amount of DAG [3].
• In addition, PA production by phospholipase D has been cited among the effects of certain oncogenes and growth factors [4].
• The strongest interactions were between alpha-synuclein and vesicles composed of 1,2-dipalmitoyl-sn-glycero-3-phosphate/1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phospho-RAC-(1-glycerol)/1,2-dipalmitoyl-sn-glycero-3-phosphocholine and involved formation of helical structure in alpha-synuclein [5].
• The greater loss of PC and increase in PA in wild-type plants as compared with PLD alpha-deficient plants may be responsible for destabilizing membrane bilayer structure, resulting in a greater propensity toward membrane fusion and cell death in wild-type plants [6].
• Incubation with PDGF-BB-activated phospholipase D (PLD) in a PKC-dependent manner resulting in the formation of phosphatidic acid (PA) [7].

Biological context of phosphatidic acid

• PA may be a significant second messenger in the activation of DNA synthesis by PDGF-BB [7].
• A quantitative molecular species analysis, using 1,2-distearoyl-sn-glycerol-3-P as internal standard, was performed by enzymatic (alkaline phosphatase) hydrolysis of PA to DAG and subsequent analysis.(ABSTRACT TRUNCATED AT 400 WORDS)[8]
• The pollen tube apical region undergoes a 46% increase in cell volume after addition of 100% water (v/v), and there is an average 7-fold increase in PA [9].
• The cellular formation of phosphatidic acid (PA) and, in the presence of ethanol, phosphatidylethanol (PEt) induced by fMLP was inhibited by TAC in a concentration-dependent manner (IC50 25.4+/-2.4 and 25.9+/-1.4 microM, respectively) [10].
• Modifications of PA level correlate with parallel changes of PLC activity, indicating a possible cross-talk between the two signal transduction pathways in the intact cell [11].

Anatomical context of phosphatidic acid

• It is produced from membrane phospholipids by either lysophosphatidate acyl-CoA:acyltransferase (lyso-PA AT) or phospholipase D. Interleukin-1 (IL-1) stimulation of human mesangial cells (HMC) induced activation of lyso-PA AT, and synthesis of new PA species with significant increase in PA mass [1].
• Guanosine-5'-O-(beta-thio)diphosphate abolished DAG and PA formation in reversibly permeabilized muscle cells [12].
• Stimulation of microsomal membranes with lipid A decreased the level of PA labeled with cis-PnA within 5 s and increased the proportion of fluorescent label in DAG [13].
• The toxin-induced DG and PA formation preceded the toxin-induced adhesion of the neutrophils to fibrinogen and fibronectin, and the production of O(2)(-) [14].
• We propose that production of PA by PLD may be required for normal microtubule organisation and hence normal growth in Arabidopsis [15].

Associations of phosphatidic acid with other chemical compounds

• In detergent cell lysates, DG kinase was readily capable of converting this surplus of DG to phosphatidic acid (PA), but in intact cells the enzyme remained inactive [16].
• Under these conditions, basal 32Pi incorporation into PIP2 and PIP but not phosphatidylinositol (PI) or PA was significantly lower in IDDM subjects [17].
• We conclude that PA is a significant signaling intermediary for IL-1 via activation of lyso-PA AT and a G-protein, which activates phosphatidate phosphohydrolase [1].
• These findings suggest that superoxide anion stimulates intestinal mitochondrial PLD resulting in PE degradation and PA formation [18].
• Insulin-induced increases in diacylglycerol (DAG) have been suggested to result from stimulation of de novo phosphatidic acid (PA) synthesis and phosphatidylcholine (PC) hydrolysis [19].

Gene context of phosphatidic acid

• These results suggest that PA and PE might help the binding of CYP3A4 to the membrane and the interaction with NPR [20].
• Mammalian target-of-rapamycin (mTOR), which is a master controller of cell growth, senses a mitogenic signal in part through the lipid second messenger phosphatidic acid (PA), generated by phospholipase D (PLD) [21].
• MMP-9 is not secreted by diacylglycerol (DAG) and an inhibitor of PA phosphatase has no effect on the secretion induced by sGITR, indicating that PA is responsible for MMP-9 secretion in murine macrophages [22].
• The PLD product PA was identified as a precursor of 'late phase' diacylglycerol which, at least in some cases, was temporally correlated and causally related to the sustained activation of PKC [23].
• Though differentially regulated by protein kinase C, both AVP-stimulated PEt and PA production required extracellular and not intracellular calcium [24].

Analytical, diagnostic and therapeutic context of phosphatidic acid

• In this report, it has been demonstrated that enhanced phospholipid metabolism through PA in tumor cells can be exploited pharmacologically for development of anticancer agents, such as CT-2584, a cancer chemotherapeutic drug candidate currently in Phase II clinical trials [4].
• Increased levels of PA were detected within 30 s and reached maximum by 15 to 30 min after treatment [9].
• With 30 min of an isoelectric EEG, levels of all phosphoinositides and PA decreased significantly; total FFA and DAG contents increased seven- and twofold, respectively; the TAG-palmitate level decreased, and that of TAG-arachidonate increased [25].
• In addition, PA levels increased 752.3% compared with control levels (from 8.6 to 64.7 micrograms/10(6) cells) with an early peak at 20 s, as measured by both HPLC and TLC (5 s, EC(50)=0.07 unit/ml) [26].

References