Phosphatidic acid, phospholipids derived

Phosphatidic acids not only are intennediates in the biosynthesis of triacylglycerols but also are biosynthetic precursors of other members of a group of compounds called phosphoglycerides or glycerol phosphatides. Phosphorus-containing derivatives of lipids are known as phospholipids, and phosphoglycerides are one type of phospholipid. 

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 ]. 

The first experiments implicating a role for PLD activity in neutrophil function were performed by Cockcroft and colleagues (Cockcroft Stutchfield, 1989 Cockcroft, 1992) who measured phosphatidic acid accumulation in cells whose membrane phospholipids or ATP were radiolabelled. These experiments showed that phosphatidic acid accumulation during cell activation did not derive from DAG, but rather was directly generated from a phospholipid. Phosphatidic acid production from DAG (generated by PLC)... 

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. 

DAG species are derived from three main routes (1) PLC-mediated hydrolysis of phospholipids (2) phosphatase-mediated hydrolysis of phosphatidic acid (PA) and (3) lipase-mediated hydrolysis of triacylglycerol (TAG) species (Fig. 2). Targeted lipidomic analyses show that the fatty acid compositions of the DAGs formed by these various routes reflect the composition of the parent lipid (Fig. 5). In particular, those derived from inositol phospholipids are highly enriched in... 

Glycerophosphatides. These lipids are mainly acyl derivatives of a-glycerophosphoric acid and often are called phospholipids. The simplest glycerophosphatides are the phosphatidic acids, which contain a-glycerophosphoric acid esterified with two fatty acids (Fig. III-37). Small quantities of phosphatidic acids have been isolated from a wide variety of plant and animal tissues. It is doubtful that these compounds exist in large amounts in tissues, because more complex glycerophosphatides are readily hydrolyzed by enzymes that are widely distributed in such tissues, yielding phosphatidic acids. Phosphatidic acid is a crucial intermediate in the biosynthesis of phospholipids. 

A kinetic analysis of recombinant hs-PLA has shown that this enzyme strongly prefers phosphatidic acid (PA) as a substrate over other phospholipids found in the mammalian plasma membrane including PS, PC and PE (70). The order of preference is PA PE approximately PS > PC. It appears that Lys-69 is at least partially involved in the PA specificity of hs-PLAj and Glu-56 in the distinction between PE and PC. These studies suggest that hs-PLA can rapidly hydrolyse PA molecules exposed to the outer layer of cell-derived microvesicles and thereby produce LPA (70). 

All glycerylphospholipids are considered as derivatives of sn-glyceryl-3-phosphoric acid that is acylated by two moieties of acjd-CoA producing 1,2-diacyl->yn-glyceryl-3-phosphoric acid. The mechanism of substitution of glyecrylphosphate of naturally occurring phospholipids produces phosphatidic acids with saturated or monounsaturated fatty acid residue in sn-l position and polyunsaturated acyl residue in sn-2 position Fig. (6). 

After ethanolamine or choline has entered a cell, it is phosphorylated and converted to a CDP derivative. Then phosphatidylethanolamine or phosphatidylcholine is formed when diacylglycerol reacts with the CDP derivative. Triacylglycerol is produced if diacylglycerol reacts with acyl-CoA. CDP-Diacylglycerol, formed from phosphatidic acid and CTP, is a precursor of several phospholipids, for example, phosphatidyl-glycerol and phosphatidylinositol. 

Many monolayer studies have been made with phospholipids and sterols which have helped to clarify the details of the molecular properties of both types of molecule required to bring about the so-called condensation effect [21-23,27]. After various speculations and suggestions, it was shown that a cis double bond at the 9,10 position of the acyl chain was not necessary for condensation, and that trans isomers and even fully saturated phospholipid could bring about this condensation effect [24]. The condensation effects are not restricted to particular phospholipid classes but have been demonstrated to occur with phosphatidylcholines and phosphatidylethanolamines as well as with phosphatidic acid [25], sphingomyelin, phosphatidylglycerol and phospholipid derivatives [26]. 

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