Phosphatidylserine biosynthesis

REGULATION OF PHOSPHATIDYLSERINE BIOSYNTHESIS AND TRANSPORT IN MAMMALIAN CELLS... 

Hasegawa, K., Kuge, O., Nishijima, M., and Akamatsu, Y., 1989, Isolation and characterization of a Chinese hamster ovary ceU mutant with altered regulation of phosphatidylserine biosynthesis. J. Biol. Chem. 264 19887-19892. 

Kuge, O., Hasegawa, K., Saito, K., and Nishijima, M., 1998, Control of phosphatidylserine biosynthesis through phosphatidylserine-mediated inhibition of phosphatidylserine synthase 1 in Chinese hamster ovary cells. Proc. Natl. Acad. Sci. USA. 95 4199-4203. 

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. 

Two routes to phospholipid biosynthesis are known in either, the participation of CTP is necessary. The first route involves phosphatidic acid in phosphoglyceride biosynthesis. Phosphatidic acid reacts with CTP to yield CDP-diglyceride which, as a coenzyme, can participate in the transfer of diglyceride onto serine (or inositol) to produce phosphatidylserine (or phosphatidylinositol). Serine phosphatides are liable to decarboxylation (pyridoxal phosphate acting... 

Once synthesized several factors influence the particular leaflet of the membrane lipid bilayer where the lipids reside. One is static interactions with intrinsic and extrinsic membrane proteins which, by virtue of their mechanism of biosynthesis, are also asymmetric with respect to the membrane. The interaction of the cytoplasmic protein, spectrin with the erythrocye membrane has been the subject of a number of studies. Coupling of spectrin to the transmembrane proteins, band 3 and glycophorin 3 via ankyrin and protein 4.1, respectively, has been well documented (van Doit et al, 1998). Interaction of spectrin with membrane lipids is still somewhat conjectural but recent studies have characterized such interactions more precisely. O Toole et al. (2000) have used a fluorescine derivative of phosphatidylethanolamine to investigate the binding affinity of specttin to lipid bilayers comprised of phosphatidylcholine or a binary mixture of phosphatidylcholine and phosphatidylserine. They concluded on the basis... 

Marggraf, W.D., and Anderer, F.A., 1974, Alternative pathways in the biosynthesis of phosphatidylserine in mouse cells.Physiol. Chem. 335 1299-1304. 

Transfer of a phosphocholine residue to the free OH group gives rise to phosphatidylcholine (lecithin enzyme l-alkyl-2-acetyl-glycerolcholine phosphotransferase 2.7.8.16). The phosphocholine residue is derived from the precursor CDP-choline (see p. 110). Phos-phatidylethanolamine is similarly formed from CDP-ethanolamine and DAG. By contrast, phosphatidylserine is derived from phosphatidylethanolamine by an exchange of the amino alcohol. Further reactions serve to interconvert the phospholipids—e.g., phosphatidylserine can be converted into phosphatidylethanolamine by decarboxylation, and the latter can then be converted into phosphatidylcholine by methylation with S-adenosyl methionine (not shown see also p. 409). The biosynthesis of phosphatidylino-sitol starts from phosphatidate rather than DAG. 

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... 

Figure 21-5 A more complete outline of the biosynthesis of triacylglycerols, glycolipids, and phospholipids including characteristic eukaryotic pathways. Green lines indicate pathways utilized by both bacteria and eukaryotes. Structures of some of the compounds are shown in Fig. 21-4. The gray arrows show the formation of phosphatidylserine by exchange with ethano-lamine (Eq. 21-10).

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... 

The final reactions for the biosynthesis of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol all occur on the cytosolic surface of the endoplasmic reticulum and Golgi apparatus (fig. 19.9). By contrast, phosphatidylglycerol and diphosphatidylglycerol are synthesized on the mitochondrial membrane where they remain for the most part. 

Bjerve, K.S. (1973). The Ca2+-dependent biosynthesis of lecithin, phosphatidylethanolamine and phosphatidylserine in rat liver subcellular particles. Biochim. Biophys. Acta 296,549-562. Bloch, F., Hansen, W.W., Packard, M. (1946). Nuclear induction. Phys. Rev. 69,127. Borkenhagen, L.F., Kennedy, E.P., Fielding, L. (1961). Enzymatic formation and decarboxylation of phosphatidylserine. J. Biol. Chem. 236, PC28-PC30. 

Biosynthesis of phosphatidylethanolamine from phosphatidylserine. The base-exchange enzyme on the cytosolic face of the endoplasmic reticulum can interconvert these phospholipids in the pre,sence of Ca and the alternate head group, serine or ethanolamine. The decarboxylase is localized in the inner membrane of mitochondria and catalyzes the nonequilibrium conversion of phosphatidylserine to phosphatidylethanolamine. 

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