Diacylglycerol synthesis

H.Y. Yu, T. Inoguchi, M. Kakimoto, N. Nakashima, M. Imamura, T. Hashimoto, F. Umeda, and H. Nawata, Saturated non-esterified fatty acids stimulate de novo diacylglycerol synthesis and protein kinase C activity in cultured aortic smooth muscle cells, Diabetologia, 2001, 44, 614—620. 

Bates, P.D., Browse, J., 2012. The significance of different diacylglycerol synthesis pathways on plant oil composition and bioengineering. Front. Plant Sci. 3,147. 

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

It has been found that the catalytic activity of PKC is enhanced by a lipid component of the cell membrane, namely phosphatidylserine. This activity is further stimulated by sn-1,2-diacylglycerol. Oleic acid also activates the enzyme in the presence of 1,2-diacylglycerol, and thus it is presumed to mimic phosphatidylserine. In order to identify that modulating binding site for oleic acid on PKC, a photoaffinity analogue was devised. A carbene generating photophore, diazirine was placed in the apolar terminus of the unsaturated fatty acid ligand (30, Fig. 12). The synthesis and the photochemical activation properties were reported by Ruhmann and Wentrup [113]. 

Anandamide is believed to be synthesized from a phospholipid precursor, /V-arachidonoyl-phosphatidylethanolamine, catalysed by phospholipase D (Di Marzo et al. 1998). The other proposed route of synthesis is from condensation of arachidonic acid and ethanolamine, although this has yet to be demonstrated in living cells. 2-AG is formed in a calcium-dependent manner, and mediated by the enzymes phospholipase C and diacylglycerol lipase (Kondo et al. 1998 Stella et al. 1997). 

Figure 1. Synthetic pathway for PS and PE in mammalian cells. The major steps occuring in the synthesis and interconversion of PS and PE are shown. The PS synthases condense serine with a phosphatidyl moiety derived from PC and PE. The nascent PS can be converted to PE by decarboxylation. PE can also be formed by transfer of a phosphoethanolamine moiety from CDP-ethanolamine to diacylglycerol via the Kennedy pathway. The abbreviations used are PC, phosphatidylcholine PS, phosphatidylserine PE, phosphatidylethanolamine DG, diacylglycerol PSD, phosphatidylserine decarboxylase PSS, PS synthase.

Figure 1. Pathways for the synthesis of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin. Abbreviations CK, choline kinase CPT, cholinephosphotransferase CT, CTP phosphooholine cytidylyltransferase DAG, diacylglycerol PC, phosphatidylcholine PE, phosphatidylethanolamine PEMT, phosphatidylethanolamine-N-methyltransferase SM, sphingomyelin SMase, sphingomyelinase SMsyn, sphingomyelin synthase.

Glycerophospholipids are used for membrane synthesis and for producing a hydrophilic surface layer on lipoproteins such as VLDL. In cell membranes, they also serve as a reservoir of second messengers such as diacylglycerol, inositol 1,4,5-triphosphate, and arachidonic acid. Their structure is similar to triglycerides, except that the last fatty acid is replaced by phosphate and a water-soluble group such as choline (phosphatidylcholine, lecithin) or inositol (phosphatidyl-inositol). 

The pathways for the synthesis of phosphoglycerides and triacylglycerol are identical up to the formation of diacylg-lycerol, after which they diverge. Hence there is an important branch-point at diacylglycerol (Figure 11.20). 

Figure 11.20 Diacylglycerol as a branch point in the synthesis of phosphoglycerides and triacylglycerol.

Figure 21.6 One mechanism of activation of the cell cycle by a growth factor. Binding of growth factor to its receptor activates membrane-bound phospholipase-C. This hydrolyses phosphati-dylinositol bisphosphate in the membrane to produce the messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 results in release of Ca from an intracellular store. The increased Ca + ion concentration activates protein kinases including protein kinase-C (PK-C). DAG remains membrane-bound and also activates protein kinase-C (PK-C) which remains in the activated form as it travels through the cell where it phosphory-lates and activates transcription factors. This results in activation of genes that express enzymes involved in nucleotide synthesis, DNA polymerases and cyclins, which are all reguired for the cell cycle (See Chapter 20 for provision of nucleotides and cyclins for the cell cycle).

Diacetylpyridine, template synthesis, 21 14 Diacylglycerol, accumulation, lithium and, 36 58... 

Mectianism of Action A combination of ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that inhibits acyl coenzyme A l,2-diacylglycerol acyltransferase and increases peroxisomal oxidation in the liver. Therapeutic Effect Reduces the synthesis of triglycerides in the liver. 

The ichthyotoxic diacylglycerol umbraculumin C (203) was isolated from the Mediterranean ophistobranch Umbraculum mediterraneum [206], The stereochemistry of compound 203 was determined by chemical interconversion and total synthesis [207]. 

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). 

In mammals, phosphatidylserine is not synthesized from CDP-diacylglycerol instead, it is derived from phosphatidylethanolamine via the head-group exchange reaction (Fig. 21-27). Synthesis of phosphatidylethanolamine and phosphatidylcholine in mammals occurs by strategy 2 of Figure 21-24 phosphorylation and activation of the head group, followed by condensation with... 

Synthesis of PE and PC from preexisting choline and ethanolamine These synthetic pathways involve the phosphorylation of choline or ethanolamine by kinases, followed by conversion to the activated form, CDP-choline or CDP-ethanolamine. Finally, choline-phosphate or ethanolamine-phosphate is transferred from the nucleotide (leaving CMP) to a molecule of diacylglycerol (see Figure 17.5). 

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

PI is synthesized from free inositol and CDP-diacylglycerol as shown in Figure 17.5. PI is an unusual phospholipid in that it olten contains stearic acid on carbon 1 and arachidonic acid on carbon 2 of the glycerol. PI, therefore, serves as a reservoir of arachidonic j acid in membranes and, thus, provides the substrate fa-prostaglandin synthesis when required (see p. 211 for a discussion of these compounds). 

Figure 11-9 Scheme showing synthesis and release of diacylglycerol and inositol phosphates and their regulation of calcium concentration in response to hormonal stimulation. 

Figure 21-3 Major pathways of synthesis of fatty acids and glycerolipids in the green plant Arabidopsis. The major site of fatty acid synthesis is chloroplasts. Most is exported to the cytosol as oleic acid (18 1). After conversion to its coenzyme A derivative it is converted to phosphatidic acid (PA), diacylglycerol (DAG), and the phospholipids phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE). Desaturation also occurs, and some linoleic and linolenic acids are returned to the chloroplasts. See text also. From Sommerville and Browse.106 See also Figs. 21-4 and 21-5. Other abbreviations monogalactosyldiacylglycerol (MGD), digalactosyldiacylglycerol (DGD), sulfolipid (SL), glycerol 3-phosphate (G3P), lysophosphatidic acid (LPA), acyl carrier protein (ACP), cytidine diphosphate-DAG (CDP-DAG).

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