Inhibition of phosphatidylcholine

Figure 3. Inhibition of phosphatidylcholine biosynthesis by apoptosis-inducing compounds. The target enzyme for the inhibition of PC biosynthesis is shown for several compounds that have further in common that they all induce apoptosis. Abbreviations are as follows CK, choline kinase CPT, cholinephosphotransferase CT, CTP phosphocholine cytidylyltransferase PC, phosphatidylcholine.

Anthony, M.L., Zhao, M., and Brindle, K.M., 1999, Inhibition of phosphatidylcholine biosynthesis following induction of apoptosis in HL-60 cells. J. Biol. Chem. 274 19686-19692... 

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. 

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). 

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. 

Houwehng, M., 1999b, Inhibition of phosphatidylcholine and phosphatidylethanolamine biosynthesis in rat-2 fibroblasts by cell-permeable ceramides. Eur. J. Biochem. 264 152-160... 

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. 

Richier, E., Biagini, G. A., Wein, S., Boudou, F., Bray, P. G., Ward, S. A., Precigout, E., Calas, M., Dubremetz, J. F., and Vial, H. J. (2006). Potent antihematozoan activity of novel bisthiazolium drug T16 Evidence for inhibition of phosphatidylcholine metabolism in erythrocytes infected with Babesia and Plasmodium spp. Antimicrob. Agents Chemother. 50,3381-3388. 

Niki, E., Kawakami, A., Yamamoto, Y. and Kamiya, Y. Oxidation of Lipids. VIII. S5mergistic inhibition of phosphatidylcholine liposome in aqueous dispersion by vitamin E and vitamin C. Bull. Chem. Soc. Jpn. 58, 1971-1975 (1985). 

It follows from the above that the neutrophil-mediated LDL oxidation may occur by both NADPH oxidase- and MPO-dependent mechanisms. It was recently demonstrated [162] that the rates of formation of phosphatidylcholine and cholesteryl ester hydroperoxides during LDL oxidation by PMA-stimulated neutrophils of MPO-knockout mice were about 66% and 44% of those by wild-type neutrophils. In both cases LDL oxidation was inhibited by SOD. These findings suggest that superoxide mediates both NADPH oxidase- and MPO-dependent pathways of oxidation by stimulated neutrophils. 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

Figure 6.19. Products of phosphatidylcholine metabolism. Phosphatidylcholine is metabolised to phosphatidic acid via the activity of phospholipase D. The phosphatidic acid generated in this way may then be converted into diacylglycerol via phosphatidate phospho-hydrolase (which is inhibited by propranolol), and the enzyme diacylglycerol kinase may regenerate the phosphatidic acid. Phospholipase D may also catalyse the transphosphati-dylation of primary alcohols, such as ethanol and butanol, at the expense of the natural substrate, phosphatidylcholine. Thus, primary alcohols can prevent phosphatidic acid production via this route.

Figure 11.21 Outline of synthesis of phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. Note in the synthesis of phosphatidylinositol, the free base, inositol, is used directly. Inositol is produced in the phosphatase reactions that hydrolyse and inactivate the messenger molecule, inositol trisphosphate (IP3). This pathway recycles inositol, so that it is unlikely to be limiting for the formation of phosphatidylinositol bisphosphate (PIP )- This is important since inhibition of recycling is used to treat bipolar disease (mania) (Chapter 12, Figure 12.9). Full details of the pathway are presented in Appendix 11.5. Inositol, along with choline, is classified as a possible vitamin (Table 15.3).

The energy state of the cell dictates the relative rates of phosphatidylcholine, phosphatidylethanolamine, and triacylglycerol biosynthesis. When energy is in short supply, the level of cAMP rises leading to inhibition of fatty acid biosynthesis (see chapter 18). This in turn decreases the supply of diacylglycerol, which limits the synthesis of phosphatidylcholine, phosphatidylethanolamine, and triacylglycerol. When sufficient diacylglycerol is pres-... 

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. 

Homan, R. and Hamelehle, K.L. 1998. Phospholipase A2 relieves phosphatidylcholine inhibition of micellar cholesterol absorption and transport by human intestinal cell line Caco-2. J. Lipid Res. 39, 1197-1209. 

The synthesis of the photoaffinity probe, NAZA-FL, lc, will be described elsewhere. The effects of this acyclic modifier on mitochondrial activities were assayed as previously described (5,6). The results are summarized in the Table. The effects, and the effective concentration range, of compounds lc and La are similar in the dark. With the photolabile modifier,< T(c, illumination with strong light resulted in an irreversible preferential inhibition of the energy-dependent proton movements this effect was not relieved by phosphatidylcholine vesicles. Hence, the modifier became covalently bonded in the vicinity of its implantation. Additional experiments were performed with phosphate-washed (12) membrane preparations (ATPase-enriched inner membrane frac-... 

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