Phosphatidylserine synthesis

Aussel, C, Pelassy, C., Breittmayer, J. P., 1998, CD95 (Fas/APO-1) induces an increased phosphatidylserine synthesis that precedes its extemalization during programmed ceU death. FEBS Lett., 431 195-199. 

In prokaryotes, phosphatidylserine is made from CDP-diacylglycerol (see fig. 19.3). The enzyme for this reaction is absent in animal cells, which rely on a base exchange reaction in which serine and ethanolamine are interchanged (fig. 19.8). Although the reaction is reversible, it usually proceeds in the direction of phosphatidylserine synthesis. Phosphatidylserine can be converted back to phos-phatidylethanolamine by a decarboxylation reaction in the mitochondria. This may be the preferred route for phosphatidylethanolamine biosynthesis in some animal cells. Furthermore these two reactions (see fig. 19.8) establish a cycle that has the net effect of converting serine into ethanolamine. This is the main route for ethanolamine synthesis... 

Buratta S., Mambrini R., Miniaci M. C., Tempia F., and Mozzi R. (2004). Group I metabotropic glutamate receptors mediate the inhibition of phosphatidylserine synthesis in rat cerebellar slices a possible role in physiology and pathology. J. Neurochem. 89 730-738. 

Voelker, D.R. 1990. Characterization of phosphatidylserine synthesis and translocation in permeabilized animal cells. J. Biol. Chem. 265 14340-14346. 

Minet, M., Dufour, M.-E. and Lacroute, F. (1992) Complementation of Saccharomyces cerevisiae auxotrophic mutants by Arabidopsis thaliana cDNAs, Plant J. 2, 417-422. Hamamatsu, S., Shibuya, I., Takagi, M. and Ohta, A. (1994) Loss of phosphatidylserine synthesis results in aberrant solute sequestration and vacuolar morphology in Saccharomyces cerevisiae, FEBS Lett. 348, 33-36. 

Breittmayer, J. P. Pelassy, C. Aussel, C. Effect of membrane potential on phosphatidylserine synthesis... 

These studies with bacteria indicate that, although animals and bacteria have a number of. similar pathways for phospholipid formation, there are several marked differences. Thus the major if not sole padiway for phosphatidylethanolamine (and phosphatidylserine) synthesis in bacteria is via CDP-diglyceride, while in animals this compound is formed from diglyceiide and CDP-ethanolamine (Keimedy and Weiss, 1956). Similarly, the major pathway for phosphatidylcholine sjmthesis in bacteria is via methylation of phosphatidylethanolamine, whereas in animals this compound is formed via diglyceride and CDP-choline (Kennedy and Weiss, 1956), as well as by methylation of phosphatidylethanolamine (Bremer and Greenberg, 1961). 

Materials. Egg phosphatidylcholine (PC), bovine brain phosphatidylserine (PS) were obtained from Avanti Polar Lipids Inc. (Birmingham, AL) and cholesterol was from Sigma (St. Louis, MO). Ganglioside GMj, bovine, was obtained from Calbiochem (San Diego, CA). Diethylenetriamine pentaacetic acid distearylamide complex (DPTA-SA) was synthesized according to ref. 17 and nlIn-DTPA-SA was prepared as described (7). This lipophilic radiolabel is not transferred to the serum components from liposomes (unpublished data), nor is it rapidly metabolized in vivo (7). The synthesis of N-(glutaryl)phosphatidylethanolamine(NGPE) has been described (18). Dipalmitoyl deoxyfluorouridine(dpFUdR) was synthesized as described (24). 

It has been found that the catalytic activity of PKC is enhanced by a lipid component of the cell membrane, namely phosphatidylserine. This activity is further stimulated by sn-1,2-diacylglycerol. Oleic acid also activates the enzyme in the presence of 1,2-diacylglycerol, and thus it is presumed to mimic phosphatidylserine. In order to identify that modulating binding site for oleic acid on PKC, a photoaffinity analogue was devised. A carbene generating photophore, diazirine was placed in the apolar terminus of the unsaturated fatty acid ligand (30, Fig. 12). The synthesis and the photochemical activation properties were reported by Ruhmann and Wentrup [113]. 

Figure 1. Control of mitochondrial biogenesis by the nuclear genome. Most mitochondrial proteins, including cytochrome c, are nuclear gene products which are subsequently imported into mitochondria. Similarly, most enzymes involved in synthesis of mitochondrial phosphoplipids are encoded in the nuclear genome. Being located in the endoplasmatic reticulum, they synthesize phosphatidylcholine (PtdCho), phosphatidylserine (PtdSer), phosphatidylglycerol (PG) and phosphatidylinositol (Ptdins). The phospholipids are transferred to the outer membrane. The imported lipids then move into the inner membrane at contact sites. Mitochondria then diversify phospholipids. They decarboxylate phosphatidylserine to phosphatidylethanolamine (PtdEtN), but the main reaction is the conversion of imported phosphatidylglycerol to cardiolipin (CL). Cardiolipins localize mainly in the outer leaflet of the inner membrane.

Figure 1. Synthetic pathway for PS and PE in mammalian cells. The major steps occuring in the synthesis and interconversion of PS and PE are shown. The PS synthases condense serine with a phosphatidyl moiety derived from PC and PE. The nascent PS can be converted to PE by decarboxylation. PE can also be formed by transfer of a phosphoethanolamine moiety from CDP-ethanolamine to diacylglycerol via the Kennedy pathway. The abbreviations used are PC, phosphatidylcholine PS, phosphatidylserine PE, phosphatidylethanolamine DG, diacylglycerol PSD, phosphatidylserine decarboxylase PSS, PS synthase.

Figure 11.21 Outline of synthesis of phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. Note in the synthesis of phosphatidylinositol, the free base, inositol, is used directly. Inositol is produced in the phosphatase reactions that hydrolyse and inactivate the messenger molecule, inositol trisphosphate (IP3). This pathway recycles inositol, so that it is unlikely to be limiting for the formation of phosphatidylinositol bisphosphate (PIP )- This is important since inhibition of recycling is used to treat bipolar disease (mania) (Chapter 12, Figure 12.9). Full details of the pathway are presented in Appendix 11.5. Inositol, along with choline, is classified as a possible vitamin (Table 15.3).

In mammals, phosphatidylserine is not synthesized from CDP-diacylglycerol instead, it is derived from phosphatidylethanolamine via the head-group exchange reaction (Fig. 21-27). Synthesis of phosphatidylethanolamine and phosphatidylcholine in mammals occurs by strategy 2 of Figure 21-24 phosphorylation and activation of the head group, followed by condensation with... 

Yeast pathways for the synthesis of phosphatidylserine, phosphatidylethanolamine, and phosphatidylglycerol are similar to those in bacteria phosphatidylcholine is formed by methylation of phosphatidylethanolamine. 

PC and PE are the most abundant phospholipids in most eukaryotic cells. The primary route of their synthesis uses choline and ethanolamine obtained either from the diet or from the turnover of the body s phospholipids. [Note In the liver, PC also can be synthesized from phosphatidylserine (PS) and PE (see below).]... 

The phospholipids in milk are synthesized by the mammary cell via pathways that are common to other mammalian cells. For further information on the synthesis of phospholipids in the mammary cell, see Kinsella and Infante (1978) and Patton and Jensen (1976). The major glycerophospholipids are phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidylinositol. A more complete composition is given in Table 4.6, Patton and Jensen (1976). The acyl and alkyl compositions will be given later. In milk, the glycerophospholipids are found predominantly in the diacyl form. However, small... 

Many of the proteins of membranes are enzymes. For example, the entire electron transport system of mitochondria (Chapter 18) is embedded in membranes and a number of highly lipid-soluble enzymes have been isolated. Examples are phosphatidylseiine decarboxylase, which converts phosphatidylserine to phosphatidylethanolamine in biosynthesis of the latter, and isoprenoid alcohol phosphokinase, which participates in bacterial cell wall synthesis (Chapter 20). A number of ectoenzymes are present predominantly on the outsides of cell membranes.329 Enzymes such as phospholipases (Chapter 12), which are present on membrane surfaces, often are relatively inactive when removed from the lipid environment but are active in the presence of phospholipid bilay-ers.330 33 The distribution of lipid chain lengths as well as the cholesterol content of the membrane can affect enzymatic activities.332... 

The formation of phosphatidylserine and possibly other phospholipids in animal tissues may also be accomplished by exchange reactions (Eq. 21-10, step a). 82 83 At the same time, decarboxylation of phosphatidylserine back to phosphatidylethanolamine (Eq. 21-10, step b) also takes place, the net effect being a catalytic cycle for decarboxylation of serine to ethano-lamine. The latter can react with CTP to initiate synthesis of new phospholipid molecules or can be converted to phosphatidylcholine (step c). However, unless there is an excess of methionine and folate in the diet, choline is an essential human nutrient.184... 

Apparently the synthesis via serine and phosphatidylserine cannot provide an adequate amount of choline, which is present in the body not only in phosphatidylcholine but in plasmalogens, sphingomyelins, and the neurotransmitter acetylcholine.185... 

Lipids also show asymmetrical distributions between the inner and outer leaflets of the bilayer. In the erythrocyte plasma membrane, most of the phosphatidylethanolamine and phosphatidylserine are in the inner leaflet, whereas the phosphatidylcholine and sphingomyelin are located mainly in the outer leaflet. A similar asymmetry is seen even in artificial liposomes prepared from mixtures of phospholipids. In liposomes containing a mixture of phosphatidylethanolamine and phosphatidylcholine, phosphatidylethanolamine localizes preferentially in the inner leaflet, and phosphatidylcholine in the outer. For the most part, the asymmetrical distributions of lipids probably reflect packing forces determined by the different curvatures of the inner and outer surfaces of the bilayer. By contrast, the disposition of membrane proteins reflects the mechanism of protein synthesis and insertion into the membrane. We return to this topic in chapter 29. 

Phosphatidylserine biosynthesis in animals is catalyzed by a base exchange enzyme on the endoplasmic reticulum. Decarboxylation of phosphatidylserine occurs in mitochondria. The cyclic process of phosphatidylserine formation from phosphatidylethanolamine and the reformation of phosphatidylethanolamine by decarboxylation has the net effect of converting serine to ethanolamine. This is a major mechanism for the synthesis of ethanolamine in many eukaryotes. 

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-... 

Letts, VA., and Henry, S.A., 1985, Regulation of phospholipid synthesis in phosphatidylserine synthase-deficient (chol) mutants of Saccharomyces cerevisiae. J. Bacteriol. 163 560-567. 

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