Phosphatidates lysophosphatidate

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

Figure 21-3 Major pathways of synthesis of fatty acids and glycerolipids in the green plant Arabidopsis. The major site of fatty acid synthesis is chloroplasts. Most is exported to the cytosol as oleic acid (18 1). After conversion to its coenzyme A derivative it is converted to phosphatidic acid (PA), diacylglycerol (DAG), and the phospholipids phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE). Desaturation also occurs, and some linoleic and linolenic acids are returned to the chloroplasts. See text also. From Sommerville and Browse.106 See also Figs. 21-4 and 21-5. Other abbreviations monogalactosyldiacylglycerol (MGD), digalactosyldiacylglycerol (DGD), sulfolipid (SL), glycerol 3-phosphate (G3P), lysophosphatidic acid (LPA), acyl carrier protein (ACP), cytidine diphosphate-DAG (CDP-DAG).

Albumin is the main plasma protein, with a molecular weight of about 69 kDa, and is important for normal plasma oncotic pressure and the transport of many biologically active substances, including free fatty acids, phospholipids (e.g., lysophosphatidic acid), prostanoids, heavy metals, steroid hormones, and vitamins. Albumin-bound lysophosphatidic acid serves as a survival factor for cultured mouse proximal tubular cells (L4). Lysophosphatidic acid is an exquisitely potent inhibitor of apoptosis, comparable with growth factors, for example, EGF. The influence of lysophosphatidic acid on the survival of tubular cells depends on the activation of phophatidylinositol 3-kinase (PI3K) with subsequent activation of Akt and pp70s6k. pp70s6k is a rapamycin-inhibited kinase, which plays an important role in the cellular proliferation. Lysophosphatidic acid also serves as a proliferation factor of mouse proximal tubular cells. Further albumin-bound factors important for the survival of the proximal tubular cells are phosphatidic acid... 

Fig. 1. Targeted lipidomics of anandamide metabolism. Postulated pathways of anandamide metabolism. Abbreviations PC, phosphatidylcholine PE, phosphatidylethanolamine NAT, JV-acyl transferase LPA, lysophosphatidic acid PA, phosphatidic acid NAPE, jV-acyl-phosphatidylethanolamine Lyso-NAPE, l-lyso,2-acyl-OT-glycero-3-phosphoethanolamine-JV-acyl ABHD-4, a//3 hydrolase-4 GP-anandamide, glycerophospho-anandamide PAEA, phospho-anandamide PLA, phospholipase A NAPE-PLD, NAPE phospholipase D PLC, phospholipase C FAAH, fatty acid amide hydrolase P, phosphatase COX, cyclooxygenase LOX, lipoxygenase CYP450, cytochrome P450 PDE, phosphodiesterase.

Fig. 2. Targeted lipidomics of 2-AG metabolism. Postulated pathways for 2-AG metabolism. Abbreviations PLC, phospholipase C DAG, diacylglycerol DGL, diacylglycerol lipase MGL, monoacylglycerol lipase PLA, phospholipase A AT, acyltransferase TAGL, triacylglycerol lipase PIP2, phosphatidylinositol bisphosphate ABHD-6/12 hydrolase lyso-PL, lysophospholipid lyso-PA, lysophosphatidic acid PA, phosphatidic add P, phosphatase COX, cydooxygen-ase LOX, lipoxygenase CYP450, cytochrome P450 CDP, cytidine diphosphate.

Platelet Activating Factor (PAF) and PAF Analogs, Lysophosphatidic Acid and Phosphatidic Acid, Phosphatidylglycerol Cardiolipin, Sphingosine-1 -P... 

Lysophosphatidic Add (lysoPA) and Phosphatidic Acid (PA) and Their Ether Analogs... 

The phosphatidic acids could potentially be found as a mixture of the 1-0-diacyl-, alkylacyl-, and alkenylacylglycerophosphoric acids. Structural characterization follows almost exactly the route as described for the lysophosphatidic acids. 

The objective in acid degumming is to chelate the calcium and magnesium ions and render the nonhydratable phosphatide forms hydratable. In addition to phosphoric acid, citric and malic acids are effective, as well as eth-ylenediaminetetraacetic acid (EDTA). Acid-treated phosphatides are not used for production of commercial lecithins. Extensive reviews on oil degumming have been prepared.106 107 Lurgi, a German equipment manufacturer, has developed an EnzyMax process that cleaves the nonhydratable phosphatides with a phospholipase B at the triglyceride s second carbon to produce a lysophosphatide that is insoluble in oil and is removed by centrifuging.108... 

Zhou D, Luini W, Bemasconi S, Diomede L, Salmona M, Man-tovani A, Sozzani S. Phosphatidic acid and lysophosphatidic acid induce haptotactic migration of human monocytes. J. Biol. Chem. 1995 270 25549. 

A concise and straightforward hydrolytic kinetic resolution of ( ) 1,1-difluoro-3,4-epoxybutylphosphonate (453) using a chiral Salen-Co complex was employed as a key step to obtain enantiomeric diols in 99% ee as important intermediates. The enantiomerically homogenous l,l-difluoro-2,3-di-hydroxypropylphosphonates (454) and (455) were converted by stereoselective esterification and deprotection into the novel phosphatase resistant analogues of lysophosphatidic acid and phosphatidic acid (456) and (457), respectively (Figure 86). ° ... 

The first acylation, catalyzed by acyl-coenzyme A-glycerol-3-phos-phate acyl transferase (GPAT), results in the formation of 1-acyl-glycer 01-3-phosphate (lysophosphatide, LPA). The LPA serves as the substrate for the second acylation reaction, catalyzed by acyl-CoA-l-acylglycerol-3-phosphate transferase (AGPAT), to form phosphatidic acid (PA). 

From work with beef-heart mitochondrial cristae and Naja Naja siamensis phospholipase A it is known that phosphatides are digested in the order phosphatidyl-ethanolamine, phosphatidylcholine and diphosphatidylglycerol (cardiolipin). The majority of the lysophosphatides seems to stay in the membrane. Low level digestion with phospholipase A, sufficient to cause almost complete breakdown of phosphatidyl-ethanolamine and phosphatidylcholine does not produce noticeable changes in membrane structure. Another Naja Naja phospholipase A preparation was also shown to attack phosphatidylethanolamine faster than phosphatidylcholine (Gallai-Hatchard and Gray, 1968)... 

Benton, A. M., Gerrard, J. M., Michiel, T., Kindom, S. E. Are lysophosphatidic acids or phosphatidic acids involved in stimulus activation coupling in platelets Blood 60 (1982) 642-649. 

Fischer, D. J., Nusser, N., Virag, T., Yokoyama, K., Wang, D., Baker, D. L., Bautista, D., Parrill, A. L., Tigyi, G. Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors. Mol Pharmacol 60 (2001) 776-784. 

Fig. 11.1 Products of phospholipase hydrolytic activity on phospholipid substrate. PC, phosphatidylcholine AA, arachidonic acid LPC, lysophosphatidic acid PA, phosphatidic acid PIP2, phosphatidylinositol 4,5-bisphosphate DAG, diacylglycerol IP3, inositol 1,4,5-trisphosphate PLA2, Phospholipase A2 PLC, Phospholipase C PLD, Phospholipase D...

Since phosphatidic acid serves as a precursor of phospholipids, galactolipids, and TGs, it is not surprising that its own synthesis has been reported in four plant compartments plastids, ER, mitochondria, and Golgi bodies. In each case, esterification of the first acyl group to the in-1 position of glycerol-3-phosphate is catalyzed by glycerol-3-phosphate acyltransferase. Lysophosphatidic acid acyltransferase then completes the synthesis by acylating the sn-2 position. However, plastidial and extraplastidial acyltransferases show distinct differences in structure and specificity. Analysis of these differences and the different compositions of plastid and non-plastid membranes led to the prokaryotic/ eukaryotic two-pathway scheme for plant lipid synthesis shown in Fig. 3. 

In the plastids, acyltransferases provide a direct route for entrance of acyl groups from ACP to membrane lipids. Since this is the standard pathway for phosphatidic acid synthesis in E. coli and cyanobacteria, both the enzymes of phosphatidic acid synthesis in plastids and the glycerolipid backbones they produce are termed prokaryotic . In both chloroplasts and non-green plastids, the glycerol-3-phosphate acyltransferase is a soluble enzyme that, unlike the E. coli enzyme, shows preference for 18 1-ACP over 16 0-ACP. The lysophosphatidic acid acyltransferase, which is a component of the inner envelope of plastids, is extremely selective for 16 0-ACP. The presence of a 16-carbon fatty acid at the... 

Fig. 5. Pathway depicting how flux through phosphatidylcholine (product of reaction 3) can promote acyl group diversity in plant triacylglycerols. Production of 18 2 (boxed) at the sn-2 position and its transfer to TG is used as a sample modification. Other fatty acid alterations may be substituted. Enzymes 1, glycerol-3-phosphate acyl-CoA acyltransferase and lysophosphatidic acid acyl-CoA acyltransferase 2, phosphatidic acid phosphatase 3, diacylglyceroliCDP-aminoalcohol aminoalcoholphosphotransferase 4, 18 l-desaturase or other fatty acid modifying enzyme 5, phosphlipid diacylglycerol acyltransferase 6, diacylglycerol acyltransferase 7, acyl-CoA phosphatidylcholine acyltransferase or phospholipase plus acyl-CoA synthetase.

Compounds 19 and 20 along with some acylated phosphatidic derivatives in addition to 1,2-dioleoylphosphatidic acid, were tested using the particle bioassay [83]. Commercially available l-oleoyl-2-lysophosphatidic acid (21) possessed repellent activity which was enhanced by monomethylation. When A. cochlioides zoospores were pre-treated with an excess of the natural stimulant N-frans-feruloyltyramine (19), and then exposed to Chromosorb W AW particles coated with various test compounds, it was found that 1 -oleoyl-2-lysophosphatidic (21, 100 ppm) and its monomethyl ester (22) (10 ppm), as well as the natural repellent 1-linoleoyl-2-lysophosphatidic acid monomethyl ester (20, 30 ppm), effectively inhibited zoospore motility [83], However, l-oleoyl-2-lysophosphatidic acid dimethyl ester (23) and 1,2-dioleoylphosphatidic acid tested with and without the stimulant (19) showed neither repellent nor motility inhibitory activity. The bioassay revealed that compounds possessing repellent activity are monoacylated phosphatidic acid derivatives containing at least one hydroxy group on the phosphoryl unit [83]. 

---