Synthesis phospholipids

Although the interior of a prokaryotic cell is not subdivided into compartments by internal membranes, the cell still shows some segregation of metabolism. For example, certain metabolic pathways, such as phospholipid synthesis and oxidative phosphorylation, are localized in the plasma membrane. Also, protein biosynthesis is carried out on ribosomes. 

ECF. Note that phosphorus is the major anion within the cells. Given this distribution, serum phosphate concentration does not accurately reflect total body phosphorus stores. Phosphorus is expressed in milligrams (mg) or millimoles (mmol), not as milliequivalents (mEq). Because phosphorus is the source of phosphate for adenosine triphosphate (ATP) and phospholipid synthesis, manifestations of phosphorus imbalance are variable. 

Copper deficiency in humans and other mammals is characterized by slow growth, hair loss, anemia, weight loss, emaciation, edema, altered ratios of dietary copper to molybdenum and other metals, impaired immune response, decreased cytochrome oxidase activity, central nervous system histopathology, decreased phospholipid synthesis, fetal absorption, and eventually death (NAS 1977 Gallagher 1979 Kirchgessner et al. 1979 USEPA 1980 ATSDR 1990 Percival 1995). 

In mammalian cells, the final stage of PS biosynthesis occurs in ER and MAM (Trotter and Voelker, 1994 Daum and Vance, 1997 Voelker, 2000). The other membranes in the ceU, such as mitochondria, nucleus, and plasma membrane, are therefore assembled from PS exported from ER and MAM (Figure 2). Phospholipid synthesis in mitochondria is restricted to the formation ofphosphatidylglycerol, cardiolipin, and PE, and other lipids such as PC and PS must be imported from sites of cellular lipid synthesis, ER or MAM (Daum, 1985 Vance, 1991). PS imported to the outer mitochondrial membrane is then translocated to the inner mitochondrial membrane, where it is converted to PE by PS decarboxylase (PSD) (Dennis and Kennedy, 1972 Voelker, 1990). It has been shown that the translocation of PS to mitochondria followed by its decarboxylation is a major pathway for the synthesis of PE in some cultured mammahan cells (Voelker, 1984 Kuge et al, 1986 Voelker and Frazier, 1986), suggesting that significant amounts of PE found in cell membranes are derived from mitochondria. 

Vance, J.E., 1990, Phospholipid synthesis in a membrane fraction associated with mitochondria. J. Biol. Chem. 265 7248-7256. 

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... 

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. 

Trans fatty acids The phospholipids in the plasma and in membranes of all cells contain long-chain polynnsatnrated fatty acids (PUFA). During periods of growth and development of organs, PUFAs are reqnired for phospholipid synthesis. The PUFAs are, of conrse, obtained from dietary triacylglycerol and phospholipids. The donble bonds in most natural fatty acids are cis not trans Nonetheless trans fatty acids do occur in dietary fats. If the diet contains trans fatty acids, they might be incorporated into the phospholipids along with the cis fatty acids and hence into membranes. The presence of these abnormal fatty acids will modify the stmctnre of the phospholipids which conld impair the fnnction of the membrane. There are two main sonrces of trans fatty acids in the diet foods produced from ruminants contain trans fatty... 

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. 

Membrane-located enzymes in the sER catalyze lipid synthesis. Phospholipid synthesis (see p. 170) is located in the sER, for example, and several steps in cholesterol biosynthesis (see p. 172) also take place there. In endocrine cells that form steroid hormones, a large proportion of the reaction steps involved also take place in the sER (see p. 376). 

Tumor necrosis factor inhibition. Ethanol (95%) extract of the rhizome, in cell culture at a concentration of 100 pg/mL, was inactive on macrophage cell line RAW 264.7 vs EPS induction of TNF-az° zp Tumor promotion inhibition. Ethyl acetate and methanol extracts of the dried rhizome, in cell culture at a concentration of 50 pg/mL, produced weak activity on G3H/ lOTl/2 cells vs tetradecanoyl phorbol acetate-induced acetate phospholipid synthesis. The hexane extract was inactiveZ . Ethanol (95%) and petroleum ether extracts of the dried rhizome, in cell culture at a concentration of 160 and 80 pg/mL, re-... 

Fig. 5. The reaction of ethanolamine-phosphate cytidylytransferase with substrates and analogues. Reaction 1 shows the normal reaction of the enzyme with ethanolamine phosphate (2-aminoethyl phosphate), which is part of the route of phospholipid synthesis. The alternative reaction with 2-aminoethylphosphonate, in parentheses, is used by some marine organisms to insert a C—P bond into their phospholipids. Reaction 2 shows the futile cycle obtained with 2-aminoethylarsonate (59). The symbol -P signifies -P03H2 and its ionized forms, and -P- signifies -P(0)(0H)- and its ionized form (61).

Honigberg MB, Brugerolle G (1990) Structure. In Honigberg BM (ed) Trichomonads parasitic in humans. Springer, New York, pp 5-35 Jungalwala FB, Dawson RMC (1970) Phospholipid synthesis and exchange in isolated liver cells. Biochem J 117 481-490... 

The mechanism of hepatotoxicity is therefore currently unclear. It has been suggested that lipid peroxidation is responsible rather than covalent binding to protein. Arylation of other low molecular weight nucleophiles such as coenzyme A and pyridine nucleotides also occurs and may be involved in the toxicity. Bromobenzene is known to cause the inhibition or inactivation of enzymes containing SH groups. It also causes increased breakdown of phospholipids and inhibits enzymes involved in phospholipid synthesis. Arylation of sites on... 

FIGURE 21-18 Phosphatidic acid in lipid biosynthesis. Phosphatidic acid is the precursor of both triacylglycerols and glycerophospholipids. The mechanisms for head-group attachment in phospholipid synthesis are described later in this section. 

In eukaryotic cells, phospholipid synthesis occurs primarily on the surfaces of the smooth endoplasmic reticulum and the mitochondrial inner membrane. Some newly formed phospholipids remain at the site of synthesis, but most are destined for other cellular locations. 

In eukaryotes, phosphatidylglycerol, cardiolipin, and the phosphatidylinositols (all anionic phospholipids see Fig. 10-8) are synthesized by the same strategy used for phospholipid synthesis in bacteria. Phosphatidylglycerol is made exactly as in bacteria. Cardiolipin synthesis in eukaryotes differs slightly phosphatidylglycerol condenses with CDP-diacylglycerol (Fig. 21-26), not another molecule of phosphatidylglycerol as in E. coli (Fig. 21-25). 

Bishop, W.R. Bell, R.M. (1988) Assembly of phospholipids into cellular membranes biosynthesis, transmembrane movement and intracellular translocation. Ararat. Rev. Cell Biol. 4, 579-610. Advanced review of the enzymology and cell biology of phospholipid synthesis and targeting. 

A classic description of the role of cytidine nucleotides in phospholipid synthesis. 

Activation of either diacylglycerol OR an alcohol by linkage to a nucleoside diphosphate (CDP) promotes phospholipid synthesis. 

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