Eukaryotes phospholipid synthesis

Comparison of eukaryotic phospholipid synthesis with that in E. coli... 

In eukaryotic cells, phospholipid synthesis occurs primarily on the surfaces of the smooth endoplasmic reticulum and the mitochondrial inner membrane. Some newly formed phospholipids remain at the site of synthesis, but most are destined for other cellular locations. 

In eukaryotes, phosphatidylglycerol, cardiolipin, and the phosphatidylinositols (all anionic phospholipids see Fig. 10-8) are synthesized by the same strategy used for phospholipid synthesis in bacteria. Phosphatidylglycerol is made exactly as in bacteria. Cardiolipin synthesis in eukaryotes differs slightly phosphatidylglycerol condenses with CDP-diacylglycerol (Fig. 21-26), not another molecule of phosphatidylglycerol as in E. coli (Fig. 21-25). 

Source of choline and ethanolamine used for phospholipid synthesis Phosphatidylethanolamine (PE) and phosphatidylcholine (PC) 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. Because the amount of choline the body makes is insufficient for its need, choline is an essential dietary nutrient. 

Figure 21-4 Biosynthesis of triacylglycerols, glycol ipids, and major phospholipids that are formed both in prokaryotes and eukaryotes. More complete schemes of phospholipid synthesis are shown in Figs. 21-3 and 21-5. Green arrow pathway occurring only in eukaryotes.

Phospholipid synthesis in eukaryotes is more complex than in E. coli. This relates to the other roles phospholipids play in membranes aside from their structural role. Eukaryotes... 

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. 

The second phase of phospholipid synthesis in eukaryotes. Choline or ethanolamine enters the cell via active transport mechanisms and is immediately phosphorylated by the enzyme, choline (ethanolamine) kinase. The phosphorylated derivatives of choline and ethanolamine... 

This chapter provides an overview of eukaryotic phospholipid biosynthesis. A discussion of phospholipid synthesis in mammalian cells is emphasized but the synthesis of phospholipids in yeast is also discussed. Phospholipid synthesis in plants is considered in Chapter 4 and in bacteria in Chapter 3. Phospholipids make up the essential milieu of cellular membranes and act as a barrier for entry of compounds into cells. Phospholipids also function as precursors of second messengers such as diacylglycerol (DG) and inositol-1,4,5-P3. A third, and usually overlooked function of phospholipids, is storage of energy in the form of fatty acyl components. This function is probably quantitatively important only under extreme conditions such as starvation. 

Transbilayer movement of lipid at the endoplasmic reticulum In eukaryotic systems a detailed pattern of synthetic asymmetry has emerged with respect to the topology of the enzymes of phospholipid synthesis in rat liver microsomal membranes. Protease mapping experiments (D.E. Vance, 1977 R. Bell, 1981) have indicated that the active sites of the phospholipid synthetic enzymes are located on the cytosolic face of the ER. Thus, in both prokaryotic and eukaryotic systems, it appears that the site of synthesis of the bulk of cellular phospholipid is the cytosolic side of the membrane. This asymmetric localization of synthetic enzymes strongly implicates transbilayer movement of phospholipids as a necessary and important event in membrane assembly that is required for the equal expansion of both leaflets of the bilayer [13]. 

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. 

Lipids have several important functions in animal cells, which include serving as structural components of membranes and as a stored source of metabolic fuel (Griner et al., 1993). Eukaryotic cell membranes are composed of a complex array of proteins, phospholipids, sphingolipids, and cholesterol. The relative proportions and fatty acid composition of these components dictate the physical properties of membranes, such as fluidity, surface potential, microdomain structure, and permeability. This in turn regulates the localization and activity of membrane-associated proteins. Assembly of membranes necessitates the coordinate synthesis and catabolism of phospholipids, sterols, and sphingolipids to create the unique properties of a given cellular membrane. This must be an extremely complex process that requires coordination of multiple biosynthetic and degradative enzymes and lipid transport activities. 

After synthesis in the various compartments of endoplasmic reticulum of alveolar type II cells, surfactant components are assembled in the cytosol into lamellar bodies. In the process of formation of lamellar bodies, the transfer of phospholipids between membranes is facilitated by phospholipid transfer proteins, which are nonenzymatic proteins found in all eukaryotic cells and which play an important role in lipid metabolism. There are three well-characterized phospholipid transfer proteins ... 

Fatty acids are not directly Incorporated Into phospholipids rather, they are first converted In eukaryotic cells Into CoA esters. The subsequent synthesis of many diacyl glycero phospholipids from fatty acyl CoAs, glycerol 3-phosphate, and polar head-group precursors Is carried out by enzymes associated with the cytosolic face of the ER membrane, usually the smooth ER, In animal cells (Figure 18-4). Mitochondria synthesize some of their own membrane lipids and Import others. In photosynthetic tissues, the chloroplast Is... 

Since phosphatidic acid serves as a precursor of phospholipids, galactolipids, and TGs, it is not surprising that its own synthesis has been reported in four plant compartments plastids, ER, mitochondria, and Golgi bodies. In each case, esterification of the first acyl group to the in-1 position of glycerol-3-phosphate is catalyzed by glycerol-3-phosphate acyltransferase. Lysophosphatidic acid acyltransferase then completes the synthesis by acylating the sn-2 position. However, plastidial and extraplastidial acyltransferases show distinct differences in structure and specificity. Analysis of these differences and the different compositions of plastid and non-plastid membranes led to the prokaryotic/ eukaryotic two-pathway scheme for plant lipid synthesis shown in Fig. 3. 

The presence of multiple membrane systems in oiganisms, such as gram-negative bacteria, photosynthetic bacteria, and the eukaryotes, raises significant questions about the mechanisms of lipid transport for membrane biogenesis. In a simple organism such as E. coli, there are two membrane systems the inner or cytoplasmic membrane and the outer membrane (Chapters 1 and 3) [14]. The entire apparatus for synthesis of phospholipids and Ra-LPS is located at the cytoplasmic face of the inner membrane. Consequently, there must exist a mechanism for exporting phospholipids and Ra-LPS from the inner membrane to the outer membrane. 

Finally, Figure 19.2 shows that CDP-diacylglycerol serves in eukaryotes as a branch point in the synthesis of phosphatidyl-inositol, yet another major phospholipid found in membranes. 

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