Harpers

METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS / 199Phosphatidate Is the Common Precursorin the Biosynthesis of Triacylglycerols,Many Phosphoglycerols, & CardiolipinBoth glycerol and fatty acids must be activated by ATPbefore they can be incorporated into acylglycerols.Glycerol kinase catalyzes the activation of glycerol tosn-glycerol 3-phosphate. If the activity of this enzyme isabsent or low, as in muscle or adipose tissue, most ofthe glycerol 3-phosphate is formed from dihydroxyacetonephosphate by glycerol-3-phosphate dehydrogenase(Figure 24–2).A. BIOSYNTHESIS OF TRIACYLGLYCEROLSTwo molecules of acyl-CoA, formed by the activationof fatty acids by acyl-CoA synthetase (Chapter 22),combine with glycerol 3-phosphate to form phosphatidate(1,2-diacylglycerol phosphate). This takes place intwo stages, catalyzed by glycerol-3-phosphate acyltransferaseand 1-acylglycerol-3-phosphate acyltransferase.Phosphatidate is converted by phosphatidatephosphohydrolase and diacylglycerol acyltransferaseto 1,2-diacylglycerol and then triacylglycerol. In intestinalmucosa, monoacylglycerol acyltransferase convertsmonoacylglycerol to 1,2-diacylglycerol in themonoacylglycerol pathway. Most of the activity ofthese enzymes resides in the endoplasmic reticulum ofthe cell, but some is found in mitochondria. Phosphatidatephosphohydrolase is found mainly in the cytosol,but the active form of the enzyme is membrane-bound.In the biosynthesis of phosphatidylcholine andphosphatidylethanolamine (Figure 24–2), choline orethanolamine must first be activated by phosphorylationby ATP followed by linkage to CTP. The resultingCDP-choline or CDP-ethanolamine reacts with 1,2-diacylglycerolto form either phosphatidylcholine orphosphatidylethanolamine, respectively. Phosphatidylserineis formed from phosphatidylethanolamine directlyby reaction with serine (Figure 24–2). Phosphatidylserinemay re-form phosphatidylethanolamineby decarboxylation. An alternative pathway in liver enablesphosphatidylethanolamine to give rise directly tophosphatidylcholine by progressive methylation of theethanolamine residue. In spite of these sources ofcholine, it is considered to be an essential nutrient inmany mammalian species, but this has not been establishedin humans.The regulation of triacylglycerol, phosphatidylcholine,and phosphatidylethanolamine biosynthesis isdriven by the availability of free fatty acids. Those thatescape oxidation are preferentially converted to phospholipids,and when this requirement is satisfied theyare used for triacylglycerol synthesis.A phospholipid present in mitochondria is cardiolipin(diphosphatidylglycerol; Figure 14–8). It is formedfrom phosphatidylglycerol, which in turn is synthesizedfrom CDP-diacylglycerol (Figure 24–2) and glycerol3-phosphate according to the scheme shown in Figure24–3. Cardiolipin, found in the inner membrane ofmitochondria, is specifically required for the functioningof the phosphate transporter and for cytochromeoxidase activity.B. BIOSYNTHESIS OF GLYCEROL ETHER PHOSPHOLIPIDSThis pathway is located in peroxisomes. Dihydroxyacetonephosphate is the precursor of the glycerol moietyof glycerol ether phospholipids (Figure 24–4). Thiscompound combines with acyl-CoA to give 1-acyldihydroxyacetonephosphate. The ether link is formed inthe next reaction, producing 1-alkyldihydroxyacetonephosphate, which is then converted to 1-alkylglycerol3-phosphate. After further acylation in the 2 position,the resulting 1-alkyl-2-acylglycerol 3-phosphate (analogousto phosphatidate in Figure 24–2) is hydrolyzed togive the free glycerol derivative. Plasmalogens, whichcomprise much of the phospholipid in mitochondria,are formed by desaturation of the analogous 3-phosphoethanolaminederivative (Figure 24–4). Plateletactivatingfactor (PAF) (1-alkyl-2-acetyl-sn-glycerol-3-phosphocholine) is synthesized from the corresponding3-phosphocholine derivative. It is formed by manyblood cells and other tissues and aggregates platelets atconcentrations as low as 10 −11 mol/L. It also has hypotensiveand ulcerogenic properties and is involved ina variety of biologic responses, including inflammation,chemotaxis, and protein phosphorylation.CDP-DiacylglycerolFigure 24–3.CMPPhosphatidylglycerol phosphateCMPPhosphatidylglycerolCardiolipin(diphosphatidylglycerol)sn-Glycerol3-phosphateH 2 OP iBiosynthesis of cardiolipin.