Phosphatidic acid synthesis

The mechanism of action and antitumor activity of 38a was studied [153]. Piericidin B1 N-oxide decreased EGF-stimulated phosphatidylinositol synthesis in a concentration dependent manner. It did not inhibit phosphatidic acid synthesis, phosphatidylinositol-4-kinasc, phospholipase C, protein kinase C, EGF receptor tyrosine kinase, EGF-induced inositol phosphate formation, DNA synthesis, RNA synthesis, or protein synthesis at concentrations which caused inhibition of phosphatidylinositol synthesis [153]. 

Phosphatidic acid synthesis prokaryotic and eukaryotic acyltransferases. 104... 

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... 

An intermediate in glycolysis, gluconeogenesis, glycerophospholipid, glycerol metabolism, phosphatidic acid synthesis, fat metabolism, and the Calvin Cycle. 

The acylation of dihydroxyacetone phosphate and the subsequent reduction of acyldihydroxacetone phosphate to monoacylphosphatidic acid provides an alternative route for phosphatidic acid synthesis. Acyltransferases which utilize dihydroxyacetone phosphate have been purified from several sources (Bell and Coleman, 1982). However, the relative contributions of dihydroxyacetone phosphate and glycerophosphate to phosphatidic acid synthesis remain controversial (O Doherty, 1978). 

A possible alternative pathway for phosphatidic acid synthesis (involving diacylglycerol kinase) has been demonstrated in rat liver (cf. Bell and Coleman, 1980) and E. coli (cf. Lennarz, 1970). However, this enzyme is probably not very important quantitatively for phosphatidic acid formation. See also Brindley and Sturton (1982) for a review of phosphatidic acid formation. 

DePaolo, R. V, and Newberne, P, M. (1971) Copper deficiency in the newborn and postnatal rat with special reference to phosphatidic acid synthesis. "Trace Substances in... 

In rat liver, phosphatidylcholine and phosphatidylethanolamine, the major phospholipid components of the mitochondrial membranes, are synthesized in the endoplasmic reticulum and are transferred to the mitochondria through a protein-mediated carrier mechanism. The mitochondria can synthesize phosphatidic acid, phosphatidylglycerol and diphosphatidyl-glycerol from glycerol-3-phosphate and can also convert phosphatidylserine to phosphatidylethanolamine by decarboxylation. The enzymes for phosphatidic acid synthesis are mainly located in the outer membrane. The details of the way in which these phospholipids become incorporated into the inner and outer mitochondrial membranes have yet to be determined. 

FIGURE 25.18 Synthesis of glycerolipids in eukaryotes begins with the formation of phosphatidic acid, which may be formed from dihydroxyace-tone phosphate or glycerol as shown. 

Tang, J.-C., Tropp, B.E., Engel, R., and Rosenthal, A.F., Isosteres of natural phosphates. 4. The synthesis of phosphonic acid analogues of phosphatidic acid and acyldihydroxyacetone phosphate, Chem. Phys. Lipids, 17, 169, 1976. 

A recent report suggests that inhibition of PC synthesis constitutes one of the primary events by which C2-ceramide triggers apoptosis (Ramos et al, 2000). Treatment of cerebral granule neurons with C2-ceramide resulted in a rapid (within 1 hour) reduction in PC biosynthesis, whereas only 6 h after exposure to the agonists the first significant drop in cell viability was observed. The authors further showed that addition of exogenous PC resulted in a dose-dependent full prevention of neuronal death. This was specific for PC, because addition of other glycerohpids Uke, PE, PS, phosphatidylinositol and phosphatidic acid had no effect on C2-ceramide-induced apoptosis. 

FIGURE 21-18 Phosphatidic acid in lipid biosynthesis. Phosphatidic acid is the precursor of both triacylglycerols and glycerophospholipids. The mechanisms for head-group attachment in phospholipid synthesis are described later in this section. 

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. 

The first phase of phospholipid synthesis in E. coli and eukaryotes. Additional routes to and from phosphatidic acid, found predominantly in eukaryotes, are shown in brackets. 

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-... 

Some General Comments. Although a number of chemical methods for the synthesis of various phosphatidic acids have been published, these procedures are often of low yield and require a deft hand for organic chemical methodology. However, there are several commercial suppliers who have available pure, well-defined phosphatidic acids for research investigations. 

Kinsella, J.E., Gross, M. 1973. Palmitic acid and initiation of mammary glyceride synthesis via phosphatidic acid. Biochim. Biophys. Acta 316, 109-113. 

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