Ethanolamine biosynthesis

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

Figure 24-2. Biosynthesis of triaq/lglycerol and phospholipids. ( , Monoacylglycerol pathway (D, glycerol phosphate pathway.) Phosphatidylethanolamine may be formed from ethanolamine by a pathway similar to that shown for the formation of phosphatidylcholine from choline.

Treatment of Rat-2 fibroblasts with various cell-permeable ceramides resulted, as discussed above, in a rapid inhibition of phospholipid synthesis. An intriguing observation was that C2-ceramides inhibited PC biosynthesis without affecting the synthesis of PE via the CDP-ethanolamine route. C2-ceramide are well known inducers of apoptosis and inhibit DNA- and protein synthesis (Obeid et al, 1993 Jayadev et al, 1995). C2-ceramide induced apoptosis in the rat-2 fibroblasts (Houweling et al, unpublished data), suggesting that inhibition of PE biosynthesis is not a prerequisite for apoptosis. 

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. 

In the synthesis of fatty acids the acetyl irnits are condensed and then are reduced to form straight hydrocarbon chains. In the oxo-acid chain elongation mechanism, the acetyl unit is introduced but is later decarboxylated. Tlius, the chain is increased in length by one carbon atom at a time. These two mechanisms account for a great deal of the biosynthesis by chain extension. However, there are other variations. For example, glycine (a carboxylated methylamine), under the influence of pyridoxal phosphate and with accompanying decarboxylation, condenses with succinyl-CoA (Eq. 14-32) to extend the carbon chain and at the same time to introduce an amino group. Likewise, serine (a carboxylated ethanolamine) condenses with... 

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... 

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. 

Additional regulation of phosphatidylcholine and phosphatidylethanolamine biosynthesis occurs at the second step in the biosynthetic sequence (see fig. 19.4) where either CDP-choline or CDP-ethanolamine are made. For phosphatidylcholine biosynthesis, the activity of CTP phos-phocholine cytidylyltransferase (which makes CDP-choline) is governed by an unusual mechanism. The enzyme... 

The lipid messenger OEA links dietary fat intake to satiety. CellMetab. 8, 281-288. Simon, G. M., and Cravatt, B. F. (2006). Endocannabinoid biosynthesis proceeding through glycer-ophospho-jV-acyl ethanolamine and a role for alpha /beta-hydrolase 4 in this pathway. J. Biol. 

Membrane proteins have a unique orientation because they are synthesized and inserted into the membrane in an asymmetric manner. This absolute asymmetry is preserved because membrane proteins do not rotate from one side of the membrane to the other and because membranes are always synthesized by the growth of preexisting membranes. Lipids, too, are asymmetrically distributed as a consequence of their mode of biosynthesis, but this asymmetry is usually not absolute, except for glycolipids. In the red-blood-cell membrane, sphingomyelin and phosphatidyl choline are preferentially located in the outer leaflet of the bilayer, whereas phosphatidyl ethanolamine and phosphatidyl serine are located mainly in the inner leaflet. Large amounts of cholesterol are present in both leaflets. 

The pronounced lag observed between labelling of the diether and tetraether polar lipids, in recent [ P]phosphate pulse-chase studies with M. thermoautotrophicum cells [62], is consistent with the generalized mechanism proposed by the authors (Fig. 4 of ref. [62] see also Fig. 13). This mechanism would account for the biosynthesis in M thermoautotrophicum of the three families of heptads of archaeol and caldarchaeol polar lipids containing P-ethanolamine, P-serine and P-inositol, since all of the... 

Biosynthesis of GPI anchors starts with the core structure assembly by sequential addition of UDP-GlcNAc (followed by iV-deacetylation), dolichol-phosphate-mannose, and phospho-ethanolamine to phosphatidylinositol and culminates in the en bloc transfer to protein shortly after the protein is synthesized. However, the biosynthetic pathways can differ strikingly between different organisms with respect to specific modifications and fatty acid remodeling occurring after completion of the core glycan. This also applies for the point when certain modifications are introduced, e. g. before or after the transfer of the GPI-moiety to the protein. GPI anchors can be cleaved at defined positions by an array of enzymatic and chemical methods, respectively (O Fig. 5). Thus, it becomes possible to identify GPI-anchored proteins and, moreover, analyze the structure and biosynthesis of GPI anchors [103]. 

Burstein and Hunter (1995) observed that THC stimulated the biosynthesis of anandamide in neuroblastoma cells employing either ethanolamine or arachidonic acid as the label. Anandamide bios5mthesis has also been shown to occur in primary cultures of rat brain neurons labelled with [H]-ethanolamine when stimulated with ionomycin, a Ca ionophore (Di Marzo et al. 1994). These authors proposed an alternate model for the biosynthesis of anandamide in which N-arachidonoyl phosphatidyl ethanolamine is cleaved by a phospholipase D activity to yield phosphatidic acid and ararchidonoylethanolamide. This model is based upon extensive studies undertaken by Schmid and collaborators (1990), who have shown that fatty acid ethanolamide formation results from the N-acylation of phosphatidyl ethanolamine by a transacylase to form N-acyl phosphatidylethanolamine. Possibly resulting from postmortem changes, this compound is subsequently hydrolyzed to the fatty acid ethanolamide and the corresponding phosphatide by a phosphodiesterase, phospholipase D. 

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. 

The a,jS-unsaturated fatty ether is an aldehydogenie group because its hydrolysis releases an a -unsaturated primary alcohol that readily tautomerizes to an aldehyde. Choline, ethanolamine, and serine plasmalogens are found in cardiac and skeletal muscle, brain, and liver. The biosynthesis of phosphatidylethanolamine is shown in Figure 19-5. 

Biosynthesis of ethanolamine plasmalogen. Enzymes (1) acyltransferase (2) synthase (3) oxidoreductase (4) acyltransferase (5) phosphatase (6) transferase (7) A -alkyl desaturase. 

Ceramides are intracellular signaling molecules implicated in the induction of cellular apoptosis (Kolesnick and Krbnke, 1998 Hannun and Luberto, 2000), and are known to induce several protein kinases and phosphatases (Mathias et al., 1991 Dobrowsky et al., 1993 Vietor et al., 1993). Ceramide analogs have been shown to inhibit PC synthesis (Bladergroen et al., 1999 Allan, 2000 Ramos et al., 2000 Vivekananda et al., 2001). Ceramides may directly affect the biosynthesis of PC and phosphatidylethanolamine (PE) by inhibiting the enzymes of the CDP-choline and CDP-ethanolamine pathways (Bladergroen et al., 1999 Awasthi et al., 2001 Ramos et al., 2002). 

Finally, GPI-anchored proteins can be metabolically radiolabeled using radiolabeled precursors for the GPI anchor biosynthesis. Lipids, myo-inositol, ethanolamine, glucosamine or mannose have all been used to incorporate a radiolabeled tag into GPI anchors [48]. 

The most likely candidate for the phosphoethanolamine donor is phosphatidylethanol-amine. Metabolic radiolabeling studies demonstrate that [ H]ethanolamine is incorporated into CDP-phosphoethanolamine before it is transferred to phosphatidylethanolamine and attached to the GPI core glycan. CDP-ethanolamine, however, is not a donor since it is not required for, nor does it affect, GPI anchor biosynthesis [62]. Consistent with this observation is the lack of [ HJglucosamine incorporation into GPI anchors in yeast mutants that do not synthesize phosphatidylethanolamine from CDP-ethanolamine yet can construct GPI anchors [88]. Direct evidence for a phosphatidylethanolamine donor is still lacking. 

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