Phosphatidylcholines synthesis

Relation of phosphatidylcholine synthesis with the sphingomyelin pathway... 

Wright, M.M., Henneberry, A.L., Lagace, T.A., Ridgway, N.D., and McMaster, C.R., 2001, Uncouphng Famesol Induced Apoptosis from its Inhibition of Phosphatidylcholine Synthesis. . Biol Chem. 276 25254-25261. 

Figure 11.7 Salvage pathway for phosphatidylcholine synthesis. (Modified from Schmidli etal., 1991.)...

Diethanolamine has been shown to inhibit choline uptake into cultured Syrian hamster embryo (SHE) and Chinese hamster ovary cells and to inhibit the synthesis of phosphatidylcholine in in-vitro systems in a concentration-dependent, competitive and reversible manner (Lehman-McKeeman Gamsky, 1999, 2000). Diethanolamine treatment caused a marked reduction in hepatic choline metabolite concentrations in mice following two weeks of dermal dosing. The most pronounced reduction was in the hepatic concentration of phosphocholine, the intracellular storage form of choline (Stott et al, 2000). Moreover, the pattern by which choline metabolites were altered was similar to the pattern of change that has been observed following dietary choline deprivation in rodents (Pomfret et al, 1990). Excess choline also prevented diethanolamine-induced inhibition of phosphatidylcholine synthesis and incorporation of diethanolamine into SHE cell phospholipids (Lehman-McKeeman Gamsky, 2000). 

Lehman-McKeeman, L.D. Gamsky, E.A. (1999) Diethanolamine inhibits choline uptake and phosphatidylcholine synthesis in Chinese hamster ovary cells. Biochem. biophys. Res. Comm., 262, 600-604... 

There are few commercial fungicides that have glycerophospholipid biosynthesis inhibition as their mode of action. The validated targets are phosphatidylcholine synthesis and phosphatidylinositol synthesis. 

FIGURE 21-28 Pathway for phosphatidylcholine synthesis from choline in mammals. The same strategy shown here (strategy 2 in Fig. 21-24) is also used for salvaging ethanolamine in phosphatidylethanolamine synthesis. 

Boggs K. P., Rock C. O., and Jackowski S. (1995). Lysophosphatidylcholine and l-O-octadecyl-2-O- methyl-rac-glycero-3-phosphocholine inhibit the CDP-choline pathway of phosphatidylcholine synthesis at the CTP phosphocholine cytidylyltransferase step. J. Biol. Chem. 270 7757-7764. 

Gasull T., DeGregorio-Rocasolano N., Zapata A., and Trullas R. (2000). Choline release and inhibition of phosphatidylcholine synthesis precede excitotoxic neuronal death but not neurotoxicity induced by serum deprivation. J. Biol. Chem. 275 18350-18357. 

Miquel, K., Pradines, A., Terce, F., Selmi, S., and Favre, G., 1998, Competitive inhibition of choline phosphotransferase by geranylgeraniol and famesol inhibits phosphatidylcholine synthesis and induces apoptosis in human lung adenocarcinoma A549 cells. JBiol Chem. 273 26179-26186... 

Choline can be used for synthesis of phosphatidylcholine by reaction between CDP-choline and diacylglycerol. Under normal conditions, the major pathway of phosphatidylcholine synthesis is by the incorporation of... 

Nakamura T, Fujiwara R, Ishiguro N et al (2010) Involvement of choline transporterlike proteins, CTL1 and CTL2, in glucocorticoid-induced acceleration of phosphatidylcholine synthesis via increased choline uptake. Biol Pharm Bull 33(4) 691-696... 

Phosphatidylcholine is degraded by phospholipases that cleave preferentially at specific bonds (Chapter 18). Choline released is phosphorylated by choline kinase and reutilized in phosphatidylcholine synthesis. However, in liver mitochondria, choline is also oxidized to betaine (N-trimethylglycine) ... 

Phosphatidylethanolamines, or cephalins (so-called because they were first obtained from brain tissue), can be synthesized by reactions analogous to those of de novo synthesis of phosphatidylcholine. Ethanolamine is first phosphorylated by ATP and ethanolamine kinase to phosphoethanolamine, which then reacts with CTP to form CDP-ethanolamine. CTPrphosphoethanolamine cytidylyltransferase is not located on the endoplasmic reticulum, nor do fatty acids activate it as they do the analogous enzyme of phosphatidylcholine synthesis. Finally, 1,2-diacylglycerol phosphoethanolamine transferase catalyses the reaction of diacylglycerol with CDP-ethanolamine to form phosphatidylethanolamine. 

Ramos, B., Salido, G.M., Campo, M.L., and Claro, E. (2000). Inhibition of phosphatidylcholine synthesis precedes apoptosis induced by C2-ceramide protection by exogenous phosphatidylcholine. Neuroreport 11, 3103-8. 

Deoxyspergualin inhibits Akt kinase activation and phosphatidylcholine synthesis. J. Biol. Chem., 277, 27765-27771. 

Gupta, C. M. and Bali, A. (1981) Carbamyl analogs of phosphatidylcholines synthesis, interaction with phospholipases and permeability behaviour of their liposomes. Biochim. Biophys. Acta 663, 506-515. 

Triglyceride and phospholipid formation. This figure depicts the formation of triacylglycerol from a-glycerolphosphate and fatty-acyl CoA. The formation of phosphatidylethanolamine and phosphatidylcholine from scratch (i.e., from serine and methionine methyl groups) is also shown. The formation of phosphatidylcholine, starting with choline, is also depicted and is the major pathway for phosphatidylcholine synthesis. 

Bodennec J., Pelled D., Riebeling C., Trajkovic S., Futerman A.H., Phosphatidylcholine synthesis is elevated in neuronal models of Gaucher disease due to direct activation of CTP phosphocholine cytidylyltransferase by glucosylceramide, Faseb J 16 (2002) 1814-1816. 

Pelech, S.L., Pritchard, P.H., Brindley, D.N.,Vance, D.E. 1983. Fatty acids promote translocation of CTP Phosphocholine cytidylyltransferase to the endoplasmic reticulum and stimulate rat hepatic phosphatidylcholine synthesis. J. Biol. Chem. 2 6782-6788. 

Phosphatidylcholine is the major phospholipid on the surface monolayer of all lipoproteins, including VLDLs. In the liver, phosphatidylcholine is synthesized by two biosynthetic pathways the CDP-choline pathway and the phosphatidylethanolamine A -methyltransferase pathway (Chapter 8). Choline is an essential biosynthetic precursor of phosphatidylcholine via the CDP-choline pathway. When cells or animals are deprived of choline, plasma levels of TG and apo B are markedly reduced and TG accumulates in the liver, resulting in fatty liver. These observations led to the widely held view that the fatty liver caused by choline deficiency is due to inhibition of PC synthesis, which in turn would decrease VLDL secretion. This hypothesis was tested in primary rat hepatocytes cultured in medium lacking choline. Upon removal of choline/methionine from culture medium, the TG content of hepatocytes was increased 6-fold, and the secretion of TG and apo B in VLDL was markedly reduced. The interpretation of these experiments was that hepatic VLDL secretion requires the synthesis of phosphatidylcholine from either the CDP-choline or methylation pathways which require choline or methionine, respectively, as precursors (D.E. Vance, 1988). However, since choline deprivation was induced in a background of methionine insufficiency, it was not clear whether the lack of choline per se, and inhibition of the choline pathway for phosphatidylcholine synthesis, decreased VLDL secretion. More recent experiments have shown, surprisingly, that deficiency of choline in primary mouse hepatocytes does not reduce, but increases, phosphatidylcholine synthesis via the CDP-choline pathway, and does not decrease VLDL secretion (J.E. Vance, 2004). Thus, a deficiency of dietary choline reduces plasma TG and apo B levels by a mechanism that does not involve reduction of phosphatidylcholine synthesis. 

To determine the role of the CDP-choline pathway of phosphatidylcholine synthesis for VLDL secretion, knockout mice were generated in which the gene encoding CTP phos-phocholine cytidylyltransferase-a (Pcytla), a key enzyme in phosphatidylcholine synthesis via the CDP-choline pathway (Chapter 8), was disrupted only in the liver. TG accumulated in livers of these mice and the secretion of TG and apo B was decreased (D.E. Vance, 2004). Thus, elimination of the CDP-choline pathway in the liver inhibits VLDL secretion. In addition, disruption of the gene encoding the liver-specific enzyme, phosphatidylethanolamine V-methyltransferase, in mice fed a high-fat/high-cholesterol diet, also markedly reduces the secretion of TG and apo B in VLDLs (D.E. Vance, 2003). Thus, the hepatic synthesis of phosphatidylcholine via both the CDP-choline and methylation pathways appears to be required for normal VLDL secretion. 

CDP is also linked to a phosphorylated form of choline to form CDP-choline in the predominant mechanism of phosphatidylcholine synthesis (Figure 19.5). Oxidation of choline to glycine betaine is one mechanism of donating a methyl group in biosynthesis of methionine (see here). 

Vision E, Colombo C, Monti S, Giulidori P and Galli C (1998) S-adenosyl-L-methionine role in phosphatidylcholine synthesis and in vitro effects on the ethanol-induced alterations of lipid metabolism. Pharmacol Res 37 203-206. 

Ansell and Spanner (1962) observed that 2-dimethylaminoethanol was phosphorylated in vivo in the brain and liver, although there was no evidence that the ester was methylated to phosphorylcholine. It was originally thought that phosphatidylcholine synthesis was being stimulated, but... 

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