Phosphatidic acid pathway

Phosphoglycerides may be synthesized either from phosphatidic add or by the so-called salvage pathway. Phosphatidic acid is also an intermediate in triglyceride biosynthesis (Figure 19.4). The phosphatidic acid pathway is relatively minor in eukaryotes phosphatidic acid reacts with CTP to form CDP diglyceride (see Figure 19.15), and the latter may then react with choline or inositol to form phosphatidylinositol or phosphatidylcholine, as in Equations (19.14) and (19.15). 

The rate of production of DAG in the cell does not occur linearly with time, but rather it is biphasic. The first peak is rapid and transient and coincides with the formation of IP3 and the release of Ca2+ this DAG is therefore derived from the PI-PLC catalyzed hydrolysis of phosphatidylinositols [1]. There is then an extended period of enhanced DAG production that is now known to be derived from the more abundant phospholipid phosphatidylcholine (PC), which has a different composition of fatty acid side chains [9]. Although DAG may be generated directly from PC through the action of PC-PLC, it can also be formed indirectly from PC. In this pathway, PC is first hydrolyzed by PLD to give choline and phosphatidic acid, which is then converted to DAG by the action of a phos-phatidic acid phosphatase [10,11 ]. 

As already mentioned, early attempts have been focused on the enzymatic production of lecithin in lecithin liposomes (Schmidli et al, 1991). The metabolic pathway was the so-called Salvage pathway, which converts glycerol-3-phosphate to phosphatidic acid, then diacylglycerol and hnally phosphatidylcholine. Production of the cell boundary from within corresponds to autopoiesis and would close the circle between minimal cell and the autopoietic view of cellular life. 

The inositol phosphates are linked into a metabolic cycle (Fig. 6.5) in which they can be degraded and regenerated. Via these pathways, the cell has the ability to replenish stores of inositol phosphate derivatives, according to demand. Ptdins may be regenerated from diacylglycerol via the intermediate levels of phosphatidic acid and CDP-glycerol. 

As in the cAMP system, multiple mechanisms damp or terminate signaling by this pathway. IP3 is inactivated by dephosphorylation diacylglycerol is either phosphorylated to yield phosphatidic acid, which is then converted back into phospholipids, or it is deacylated to yield arachidonic acid Ca2+ is actively removed from the cytoplasm by Ca2+ pumps. 

The first steps of glycerophospholipid synthesis are shared with the pathway to triacylglycerols (Fig. 21-17) two fatty acyl groups are esterified to C-l and C-2 of L-glycerol 3-phosphate to form phosphatidic acid. Commonly but not invariably, the fatty acid at C-l is saturated and that at C-2 is unsaturated. A second route to phosphatidic acid is the phosphorylation of a diacyl-glycerol by a specific kinase. 

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).

Synthesis of most phospholipids starts from glycerol-3-phosphate, which is formed in one step from the central metabolic pathways, and acyl-CoA, which arises in one step from activation of a fatty acid. In two acylation steps the key compound phosphatidic acid is formed. This can be converted to many other lipid compounds as well as CDP-diacylglycerol, which is a key branchpoint intermediate that can be converted to other lipids. Distinct routes to phosphatidylethanolamine and phosphatidylcholine are found in prokaryotes and eukaryotes. The pathway found in eukaryotes starts with transport across the plasma membrane of ethanolamine and/or choline. The modified derivatives of these compounds are directly condensed with diacylglycerol to form the corresponding membrane lipids. Modification of the head-groups or tail-groups on preformed lipids is a common reaction. For example, the ethanolamine of the head-group in phosphatidylethanolamine can be replaced in one step by serine or modified in 3 steps to choline. 

In the first phase of phospholipid synthesis from glyc-erol-3-phosphate to phosphatidic acid, the pathways in E. coli and eukaryotes are very similar (see fig. 19.2). The major difference is that one additional pathway exists for generation of phosphatidic acid from dihydroxyacetone phosphate, an intermediate in glycolysis. Once phosphatidic acid is made, it is rapidly converted to diacylglycerol or CDP-diacylglycerol (see fig. 19.2) both of which are intermediates for the biosynthesis of eukaryotic phospholipids. 

Lipid synthesis is unique in that it is almost exclusively localized to the surface of membrane structures. The reason for this restriction is the amphipathic nature of the lipid molecules. Phospholipids are biosynthesized by acylation of either glycerol-3-phosphate or dihydroxyacetone phosphate to form phosphatidic acid. This central intermediate can be converted into phospholipids by two different pathways. In one of these, phosphatidic acid reacts with CTP to yield CDP-diacylglycerol, which in bacteria is converted to phosphatidylserine, phosphatidylglycerol, or diphos-... 

Fig. 20.3. Schematic representation of the main pathways in the lipid metabolism of parasitic flatworms. Boxed substrates are supplied by the host. Pathways present in mammalian systems but absent in parasitic flatworms are shown by open arrows. Abbreviations DAG, diacylglycerol CDP-DAG, cytidine diphosphodiacylglycerol Farnesyl PP, farnesyl pyrophosphate Geranyl PP, geranylpyrophosphate Geranylgeranyl PP, geranylgeranylpyrophosphate FlMG-CoA, hydroxymethylglutaryl-CoA TAG, triacylglycerol PA, phosphatidic acid PC, phosphatidylcholine PE, phosphatidylethanolamine PI, phosphatidylinositol PS, phosphatidylserine.

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.

During hormonal stimulation of Ptdlns 4,5-P2 hydrolysis there appears to be a preferential degradation of molecules, such as diacylglycerol and phosphatidic acid, which contain arachidonate in the 2-position. Two separate pathways have been proposed for the release of arachidonic acid from these two products of the phosphoinositide response. The first proposes that diacylglycerol is the source of the liberated arachidonate and that diacylglycerol lipase acts on the DG released by hydrolysis of phosphoinositides. The second suggests that a phosphatidic acid-specific phospholipase A2 is responsible for cleaving the arachidonic acid from phosphati-date. 

The use of AIF41 in the investigation of canine cerebral cortex [40] led to the discovery of a previously unrecognized signaling pathway in the brain. These experiments demonstrated that muscarinic acetylcholine receptor-G-protein uses PLD as the effector enzyme. AlF41 caused a two- to three-fold increase in breakdown of phosphatidylcholine and rapid accumulation of choline and phosphatidic acid was observed. 

Park, J., Gu, Y., Lee, Y., Yang, Z. and Lee, Y., 2004, Phosphatidic acid induces leaf cell death in Arabidopsis by activating the Rho-related small G protein GTPase-mediated pathway of reactive oxygen species generation. Plant Physiol. 134 129-136. 

The pathway for formation of DG from TG in the fat body is unknown. The lipolytic activity in fat body homogenates from L. migraloria (Tietz and Weintraub, 1978) and M. sexta (Arrese and Wells, 1992) converts TG primarily to free fatty acids (FFAs), whereas in the desert locust Schisto-cerca gregaria (Spencer and Candy, 1976) and the cockroach P. americana (Hoffman and Downer, 1979b) the end products were DG and FFA. Micro-somes from the L. migratoria fat body can acylate 2-MG to produce DG (Tietz et al., 1975). It has been shown that the DG released from the fat body has the 5n-l,2 configuration (Lok and Van der Horst, 1980 Tietz and Weintraub, 1980), therefore either a pathway involving de novo synthesis of DG via phosphatidic acid or the stereospecific hydrolysis of TG could be involved. 

Fatty acyl CoA combines with glycerol 3-phosphate in the liver to form triacylglycerols by a pathway in which phosphatidic acid serves as an intermediate. 

In addition to PL A2-mediated mechanisms, it is worth noting that A A can also be generated from the activation of other pathways, including PLC, which forms DAG that could be cleaved to generate AA via the action of mono- or diglycerol lipase (194). PLD-mediated cleavage of phosphatidylcholine may also generate phosphatidic acid (PA), which can be further metabolized by phosphatidic acid phosphohydrolase to DAG, and activation of AA release by arARs via the PLD pathway has been reported (196). 

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