Phosphatidylethanolamine metabolism

Radioautography was applied also to the study of lecithin and phosphatidylethanolamine metabolism in the liver. In those studies use was made of liver slices, which permitted to carry out a pulse-chase type of experiment (O. Stein and Stein, 1969). Before discussing the results obtained it is pertinent to point out certain restrictions which were imposed on the experimental design. In order to label selectively lecithin molecules, use had to be made of labeled choline, which can represent only one pathway of lecithin synthesis and in addition suffers from the drawback that it supposedly may also be incorporated into the lecithin molecule not by de novo synthesis, but by exchange. This view is held by Treble et al. (1970), but has not been supported by experimental data of Nagley and Hallinan (1968) and of O. Stein and Stein (1969). 

Materials. Egg phosphatidylcholine (PC), bovine brain phosphatidylserine (PS) were obtained from Avanti Polar Lipids Inc. (Birmingham, AL) and cholesterol was from Sigma (St. Louis, MO). Ganglioside GMj, bovine, was obtained from Calbiochem (San Diego, CA). Diethylenetriamine pentaacetic acid distearylamide complex (DPTA-SA) was synthesized according to ref. 17 and nlIn-DTPA-SA was prepared as described (7). This lipophilic radiolabel is not transferred to the serum components from liposomes (unpublished data), nor is it rapidly metabolized in vivo (7). The synthesis of N-(glutaryl)phosphatidylethanolamine(NGPE) has been described (18). Dipalmitoyl deoxyfluorouridine(dpFUdR) was synthesized as described (24). 

Today s mitochondria lack most of the genes involved in phosphohpid metabolism. Therefore, mitochondria have to import most of their hpids. Phospholipids such as phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol must be synthesized in the endoplasmatic reticulum under the control of nuclear genes and then transferred to mitochondria (Voelker, 2000) (Figure 1). Mitochondria use both nuclear and mitochondrial encoded proteins to further diversify phospholipids (Dowhan, 1997 Kent, 1995 Daum, 1985). Thus, a nuclear phosphatidylserine decarboxylase converts phosphatidylserine into phosphatidylethanolamine, or mitochondrial encoded cardiolipin synthase converts phosphatidylglycerol into cardiolipin which is incorporated exclusively into the inner mitochondrial membrane. 

Mizuguchi, H., Kudo, N., Ohya, T. Kawashima, Y. (1999) Effects of tiadenol and di-(2-ethyl-hexyl)phthalate on the metabolism of phosphatidylcholine and phosphatidylethanolamine in the liver of rats comparison with clofibric acid. Biochem. Pharmacol, 57, 869-876 Mocchiutti, N.O. Bernal, C.A. (1997) Effects of chronic di(2-ethylhexyl) phthalate intake on the secretion and removal rate of triglyceride-rich lipoproteins in rats. Food chem. Toxicol, 35, 1017-1021... 

Several studies have evaluated the effects of oral di(2-ethylhexyl) adipate on various aspects of hepatic lipid metabolism. Feeding di(2-ethylhexyl) adipate (2% of diet) to male Wistar rats for seven days resulted in increased hepatic fatty acid-binding protein as well as in increased microsomal stearoyl-CoA desaturation activity (Kawashima et al., 1983a,b). Feeding the compound at this dose for 14 days resulted in increased levels of hepatic phospholipids and a decline in phosphatidyl-choline phosphatidylethanolamine ratio (Yanagita et al., 1987). Feeding di(2-ethyl-hexyl) adipate (2% of diet) to male NZB mice for five days resulted in induction of fatty acid translocase, fatty acid transporter protein and fatty acid binding protein in the liver (Motojima et al., 1998). 

Some of the earlier data tabulated by Morrison (1970) on the fatty acid compositions of milk phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin are shown in Table 4.10. Included are analyses by Boatman et al. (1969) on phosphatidylethanolamine and phosphati-dylserine and by Bracco et al (1972) on phosphatidylinositol. The differences in composition between the samples of phosphatidylethanolamine and -serine can be attributed primarily to differences in metabolism. 

Synthesis of most phospholipids starts from glycerol-3-phosphate, which is formed in one step from the central metabolic pathways, and acyl-CoA, which arises in one step from activation of a fatty acid. In two acylation steps the key compound phosphatidic acid is formed. This can be converted to many other lipid compounds as well as CDP-diacylglycerol, which is a key branchpoint intermediate that can be converted to other lipids. Distinct routes to phosphatidylethanolamine and phosphatidylcholine are found in prokaryotes and eukaryotes. The pathway found in eukaryotes starts with transport across the plasma membrane of ethanolamine and/or choline. The modified derivatives of these compounds are directly condensed with diacylglycerol to form the corresponding membrane lipids. Modification of the head-groups or tail-groups on preformed lipids is a common reaction. For example, the ethanolamine of the head-group in phosphatidylethanolamine can be replaced in one step by serine or modified in 3 steps to choline. 

Fig. 20.3. Schematic representation of the main pathways in the lipid metabolism of parasitic flatworms. Boxed substrates are supplied by the host. Pathways present in mammalian systems but absent in parasitic flatworms are shown by open arrows. Abbreviations DAG, diacylglycerol CDP-DAG, cytidine diphosphodiacylglycerol Farnesyl PP, farnesyl pyrophosphate Geranyl PP, geranylpyrophosphate Geranylgeranyl PP, geranylgeranylpyrophosphate FlMG-CoA, hydroxymethylglutaryl-CoA TAG, triacylglycerol PA, phosphatidic acid PC, phosphatidylcholine PE, phosphatidylethanolamine PI, phosphatidylinositol PS, phosphatidylserine.

Fig. 1. Targeted lipidomics of anandamide metabolism. Postulated pathways of anandamide metabolism. Abbreviations PC, phosphatidylcholine PE, phosphatidylethanolamine NAT, JV-acyl transferase LPA, lysophosphatidic acid PA, phosphatidic acid NAPE, jV-acyl-phosphatidylethanolamine Lyso-NAPE, l-lyso,2-acyl-OT-glycero-3-phosphoethanolamine-JV-acyl ABHD-4, a//3 hydrolase-4 GP-anandamide, glycerophospho-anandamide PAEA, phospho-anandamide PLA, phospholipase A NAPE-PLD, NAPE phospholipase D PLC, phospholipase C FAAH, fatty acid amide hydrolase P, phosphatase COX, cyclooxygenase LOX, lipoxygenase CYP450, cytochrome P450 PDE, phosphodiesterase.

Methionine is intimately related to lipid metabolism in the liver. Methionine deficiency is one of the causes of the fatty liver syndrome. Lack of methionine prevents the methylation of phosphatidylethanolamine to phosphatidylcholine, resulting in an ability by the liver to build and export very low density lipoprotein. The syndrome can be treated by the administration of choline, and for this reason, choline has often been referred to as the lipotropic factor. 

All the cosubstrates that occur in drug conjugation (Figure 2.28) have other roles in metabolism e.g., UDP-glucuron-ic acid and PAPS provide acidic groups for the S5mthesis of mucopolysaccharides, whereas S-adenosylmethionine provides methyl groups for the synthesis of phosphatidylcholine from phosphatidylethanolamine. 

Pyridoxal phosphate has a clear role in lipid metabolism as the coenzyme for the decarboxylation of phosphatidylserine, leading to the formation of phosphatidylethanolamine, and then phosphatidylcholine (Section 14.2.1), and membrane lipids from vitamin Bg-deficient animals are low in phosphatidylcholine (She et al., 1995). It also has a role, less well defined, in the metabolism of polyunsaturated fatty acids vitamin Bg deficiency results in reduced activity of A desaturase and impairs the synthesis of eicosapentanoic and docosahexanoic acids (Tsuge et al., 2000). 

A number of the products of the decarboxylation of amino acids shown in Table 9.2 are important as neurotransmitters and hormones, such as dopamine, noradrenaline, adrenaline, serotonin (5-hydroxytryptamine), histamine, and Y - aminobutyric acid (GABA), and as the diamines agmatine andput-rescine and the polyamines spermidine and spermine, which are involved in the regulation of DNA metabolism. The decarboxylation of phosphatidylser-ine to phosphatidylethanolamine is important in phospholipid metabolism (Section 14.2.1). 

Almost all body cells contain phospholipids. The common animal phospholipids are made of sphingomyelin, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and other glycerol phospholipids of complex fatty acid composition. PC, formerly referred to as lecithin, PE, formerly referred to as cephalin, and PS are by far the most predominant phospholipids from most animal sources. As constituents of cell walls and active participants in metabolic processes, they appear to be essential to life (8). 

The most likely candidate for the phosphoethanolamine donor is phosphatidylethanol-amine. Metabolic radiolabeling studies demonstrate that [ H]ethanolamine is incorporated into CDP-phosphoethanolamine before it is transferred to phosphatidylethanolamine and attached to the GPI core glycan. CDP-ethanolamine, however, is not a donor since it is not required for, nor does it affect, GPI anchor biosynthesis [62]. Consistent with this observation is the lack of [ HJglucosamine incorporation into GPI anchors in yeast mutants that do not synthesize phosphatidylethanolamine from CDP-ethanolamine yet can construct GPI anchors [88]. Direct evidence for a phosphatidylethanolamine donor is still lacking. 

If SIP is not secreted or dephosphorylated by specific SIP phosphatases, as well as by more general lipid phosphatases, it is cleaved irreversibly to ethanolamine phosphate and rrans-2-hexadecenal by SIP lyase (J. Zhou, 1998 P.P. Van Veldhoven, 20(X)). As shown first in the 1970s by W. Stoffel and coworkers, the phosphoethanolamine can be utilized for the synthesis of phosphatidylethanolamine (Chapter 8), and fran5-2-hexadecenal can be reduced to the alcohol and incorporated into alkyl ether lipids. Under certain conditions, degradation of sphingoid bases can account for as much as one-third of the ethanolamine in phosphatidylethanolamine (E.R. Smith, 1995). It is interesting that both the first enzyme of sphingoid base metabolism (SPT) and the last enzyme, the lyase, are pyridoxal 5 -phosphate-dependent. 

MTD was incorporated preferentially into triacylglycerols rather than into phospholipids. The proportion of 13-MTD in both phospholipids and triacylglycerols increased to saturation level in 6 h of incubation. The metabolic fate of fatty acids thus showed diversity with their chemical structures and resulted in uneven positional distribution in triacylglycerol or phospholipid molecules [35], Triacylglycerols contained almost equal proportions of 13-MTD at the sn-2 position and at the sn-1,3 positions. 13-MTD was incorporated into phosphatidylcholine to a greater extent than into phosphatidylethanolamine, with preference for the sn-2 position. 

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