CDP-ethanolamine pathway

PE can be generated by several mechanisms. The CDP-ethanolamine route may be important under physiological conditions in vivo when an abundant supply of ethanolamine is present. The CDP-ethanolamine pathway is very similar to the CDP-choline pathway described above (Tijburg et al. 1989 Bladergroen and Van Golde, 1997). The pathway comprises (i) an ethanolamine kinase (EK) which converts ethanolamine to phosphoethanolamine, (ii) an CTP phosphoethanolamine cytidyltransferase... 

FIGURE 6.2 Phosphatidylcholine (PC) synthesis by the CDP-ethanolamine pathway. Structures of ethanolamine and choline. The nucleotide moiety S-adenosyl methionine (SAM) is requiivct to transfer the methyl group of methionine to phosphatidylethanolamine (J E) to form PC. In the process, SAM is converted to S-adenosyl homocysteine (SAH). The nitrogen atom of PC has four covalent bonds and is called a quaternary amine. It bears a positive charge that is not influenced by changes in the pH of the suitoimding fluids. The PE methyltran.sferase pathway of I C synthesis occurs only in the liver. 

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). 

The biosynthesis of PE in eukaryotic cells can occur by four pathways (Figs. 1 and 7). The CDP-ethanolamine pathway represents the de novo synthesis of PE as first described by Kennedy and Weiss in 1956. The other pathways for PE biosynthesis involve... 

The reactions of the CDP-ethanolamine pathway (Figs. 1 and 7) parallel those of the CDP-choline pathway for PC synthesis (Section 3). Ethanolamine is an obligatory precursor of PE synthesis by this route and is derived from the diet with smaller amounts... 

The second step in the CDP-ethanolamine pathway is catalyzed by CTP phospho-ethanolamine cytidylyltransferase (ET) which converts phosphoethanolamine to CDP-ethanolamine (Figs. 1 and 7). The enzyme is located primarily in the cytosol but has also been detected in rough ER membranes by immunoelectron microscopy. ET is distinct from CT and is not activated by lipids. There is no report of ET, unlike CTa (Section... 

In the final reaction of the CDP-ethanolamine pathway, PE is made by reaction between CDP-ethanolamine and DG via CDP-ethanolamine 1,2-DG ethanolaminephospho-transferase (Figs. 1 and 7), an integral membrane protein that resides primarily on ER membranes and to a lesser extent on membranes of the Golgi and MAM. The enzyme has a distinct preference for DG species that contain l-palmitoyl-2-docosahexaenoyl (22 6) acyl chains. In cultured hepatocytes, nearly 50% of PE made by the CDP-ethanolamine pathway is this species the function of this striking selectivity is unknown. Mutants of... 

S. cerevisiae have been generated that are deficient in an ethanolaminephosphotrans-ferase activity that has dual specificity for both CDP-ethanolamine and CDP-choline and generates PE and PC, respectively (R.M. Bell, 1991). The human ortholog of this gene was cloned and encodes a choline/ethanolaminephosphotransferase activity that was predicted to be solely responsible of the final reaction of PE synthesis via the CDP-ethanolamime pathway (C.R. McMaster, 1999). However, recently, another human cDNA was identified that encodes ethanolaminephosphotransferase activity. This enzyme appears to be specific for CDP-ethanolamine and is likely involved in PE synthesis via the CDP-ethanolamine pathway (Y. Hirabayashi, 2007). 

Very little information is available on the mechanisms that control the production of PE via the CDP-ethanolamine pathway. Factors that regulate this pathway for PE production at the level of gene expression have not yet been elucidated. In the 1970s Akesson and Sundler reported that ET catalyzes the rate-limiting step of this pathway (R. Sundler, 1975). In addition, under some metabolic conditions the supply of the substrate, DG, can limit the rate of PE biosynthesis from ethanolamine (L.M.G. van Golde, 1989). Two studies have implicated a channeling of intermediates of the pathway in the biosynthesis of PE in mammalian cells (M.W. Spence, 1989). 

Lykidis, A. Wang, J. Karim, M.A. Jackowski, S. Overexpression of a mammalian ethanolamine-specific kinase accelerates the CDP-ethanolamine pathway. J. Biol. Chem., 276, 2174-2179 (2001)... 

Phosphatidylethanolamine can be formed in four ways (Table 7.2). Again, the CDP-ethanolamine pathway is the most active pathway in animals and plants. However, the ethanolamine which is needed for this pathway derives from the decarboxylation of serine and that reaction can only, apparently, take place on a lipid substrate (i.e. phosphatidylserine) in animal tissues. Thus the decarboxylation of phosphatidylserine (method 2) assumes importance not only as a source of phosphatidylethanolamine directly but also to provide ethanolamine. In addition, ethanolamine can be liberated by the catabolism of sphingolipids. The decarboxylation of phosphatidylserine is the method by which bacteria produce phosphatidylethanolamine. The other two pathways (methods 3 and 4) are of minor overall significance but may be used for specialist purposes, e.g. method 4 is used for the formation of molecular species which are poorly formed by the CDP-base pathway. 

---