Phospholipid synthesis regulation

Recently, it has been shown that cell-permeable cerantides dramatically inhibited the synthesis of the two major membrane phospholipids, PC and PE (Bladergroen et al, 1999b Allan, 2000). The inhibition of phospholipid synthesis was rapid, within 2 h, and resulted in massive apoptosis after 16-24 h. The mechanism by which short-chain cerantides exert their effect on phospholipid synthesis is possibly cell type dependent. In baby-hamster kidney (BHK) fibroblasts rc synthesis was reduced at the level of CT, the putative rate-determining enzyme in the CDP-choline pathway (Allan, 2000). This conclusion was based solely on radio-label studies in combination with an earlier published observation (Wieder et al, 1995) showing that C2-SM (the SM generated from C2-ceramide by SM synthase, which was actively synthesized in the BHK-cells) inhibited CT activity in vitro. On the other hand, data obtained from studies with rat-2 fibroblasts clearly showed that short-chain cerantides regulate the synthesis of PC and PE mainly at the final step of the CDP-pathways. This conclusion was based on the following observations (a) incorporation of [ H]-choline into PC and... 

The cycle makes available essential fatty acids that are required for the phospholipid synthesis necessary for new membrane formation in the proliferating tumour cells (Figure 21.22) and for synthesis of eicosanoids for regulation of proliferation. Such factors are also required by proliferating immune ceUs that may attack tumour cells, so that there will be competition for essential fatty acids between immune and tumour cells. 

Hirsch, J.R, and Henry, S.A., 1986, Expression of the Saccharomyces cerevisiae inositol-1-phosphate synthase (inol) gene is regulated by factors that affect phospholipid synthesis. Mol. Cell Biol. 6 3320-3328. 

Griac, P., and Henry, S.A., 1996, Phosphatidylcholine biosynthesis in Saccharomyces cerevisiae Effects on regulation of phospholipid synthesis and respiratory competence. In Op den Kamp, J.A.F. (ed.), NATO ASI Series Molecular Dynamics of Biological Membranes. Springer, Verlag, pp. 339-346. 

Letts, VA., and Henry, S.A., 1985, Regulation of phospholipid synthesis in phosphatidylserine synthase-deficient (chol) mutants of Saccharomyces cerevisiae. J. Bacteriol. 163 560-567. 

Lipogenesis, the synthesis of lipids from carbohydrate via acetyl-CoA, occurs almost exclusively in the liver cells and the fatty tissue, (s. fig. 3.9) According to lipid topogenesis (4), the enzymes involved in triglyceride and phospholipid synthesis are localized on the cytoplasmic surface of the endoplasmic reticulum. The level of hepatic synthesis is regulated primarily by the insulin-glucagon quotient, as described by R.H. Unger in 1971. 

Coordinate regulation of fatty acid and phospholipid synthesis with macromolecular biosynthesis... 

Fig. 10. Coordinate regulation of fatty acid and phospholipid metabolism. The pleiotropic regulator ppGpp regulates transfer of fatty acids to the membrane via inhibition of the PlsB acyltransferase step, coordinating phospholipid synthesis with macromolecular synttesis. PlsB inhibition leads to the accumulation of long-chain acyl-ACPs that feedback inhibit their own synthesis at the point of initiation (inhibition of acetyl-CoA carboxylase and FabH) and elongation, by inhibition of Fabl. LPA, lysophosphatidic acid G3P, glycerol-3-phosphate.

Carman, G.M., Han, G.S. 2007. Regulation of phospholipid synthesis in Saccharomyces cerevisiae by zinc depletion. Biochim. Biophys. Acta 1771 322-330. 

They are especially abundant in many parasitic protozoa and may carry additional glycosyl groupsT Regulation of phospholipid synthesis, which has been studied in detail in yeast, is complex but highly coordinated. The committed step in the synthesis of PE and PC is the hydrolysis of phosphatidafe (PA) by a phosphafase to generate diacylglycerols (Fig. 

Regulation of phospholipid synthesis could occur In many forms. These Include compartmentallzatlon, regulation of substrate levels, control of the Ionic environment, control of the phospholipids associated with key enzymes, and others. Several aspects of regulation of phospholipid synthesis, along with some recent advances In these areas, are discussed below. 

Therefore, it is currently believed that anandamide is formed from membrane phospholipids (Fig. 4) through a pathway that involves (1) a trans-acylation of the amino group of phosphatidylethanolamine with arachidonate from the sn-1 position of phosphatidylcholine and (2) a D-type phosphodiesterase activity on the resulting A-arachidonylphosphati-dylethanolamide (NAPE). Synthesis of anandamide is presumably regulated at the levels of both enzymes, the A-acyltranferase and the phospholipase D, by stimuli that raise intracellular calcium or by receptors linked with cAMP and PKA. It has been shown that anandamide is formed when neurons are depolarized and, therefore, the intracellular calcium ion levels are elevated (Cadas, 1996). 

Fig. 10.7 RNA synthesis in vesicles. Membrane permeability can be regulated by choosing the correct chain length of the fatty acids in the phospholipids. Short chains (a) make the bilayer so unstable that even large molecules such as proteases can enter the vesicle interior and damage the polymerase. Carbon chains which are too long (b) prevent the entry of substrate molecules such as ADR RNA polymerisation in the vesicle occurs only with C14 fatty acids (c)...

A summary of some of these processes is as follows synthesis of phospholipids and cholesterol de novo synthesis of ribonucleotides synthesis of RNA de novo synthesis of deoxyribonucleotides regulation of synthesis of deoxyribonucleotides salvage pathways duplication of DNA transcription and translation (polypeptide synthesis). After this series of topics, those of fuels and ATP generation, mitosis and, finally, regulation of the cycle, are described and discussed. 

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