Biochemistry, 4th Edition P78 docx

24.1 How Are Fatty Acids Synthesized? 733 C 16 Fatty Acids May Undergo Elongation and Unsaturation Additional Elongation As seen already, palmitate is the primary product of the fatty acid synthase. Cells synthesize many other fatty acids. Shorter chains are eas- ily made if the chain is released before reaching 16 carbons in length. Longer chains are made through special elongation reactions, which occur both in the mitochondria and at the surface of the endoplasmic reticulum (ER). The ER re- actions are actually quite similar to those we have just discussed: addition of two- carbon units at the carboxyl end of the chain by means of oxidative decarboxyla- tions involving malonyl-CoA. As was the case for the fatty acid synthase, this decarboxylation provides the thermodynamic driving force for the condensation reaction. The mitochondrial reactions involve addition (and subsequent reduc- tion) of acetyl units. These reactions (Figure 24.12) are essentially a reversal of fatty acid oxidation, with the exception that NADPH is utilized in the saturation of the double bond, instead of FADH 2 . Introduction of a Single cis Double Bond Both prokaryotes and eukaryotes are capable of introducing a single cis double bond in a newly synthesized fatty acid. Bacteria such as E. coli carry out this process in an O 2 -independent pathway, whereas eukaryotes have adopted an O 2 -dependent pathway. There is a fundamen- tal chemical difference between the two. The O 2 -dependent reaction can occur any- where in the fatty acid chain, with no (additional) need to activate the desired bond toward dehydrogenation. However, in the absence of O 2 , some other means must be found to activate the bond in question. Thus, in the bacterial reaction, dehy- drogenation occurs while the bond of interest is still near the ␤-carbonyl or ␤-hydroxy group and the thioester group at the end of the chain. C CH 2 R S CoA CCH 2 CH 2 R C S CoA C H OH CH 2 CH 2 R C S CoA C H H CH 2 C R C S CoA CH 2 CH 2 CH 2 R C S CoA C O CH 3 CoA S O O O O O O H + 1 4 2 3 Acyl-CoA Acyl-CoA (2 carbons longer) Thiolase HSCoA ␤ -Ketoacyl-CoA L- ␤ -hydroxyacyl-Co A dehydrogenase L- ␤ -Hydroxyacyl-CoA ␣ , ␤ -trans-Enoyl-CoA Enoyl-CoA hydratase NADH + NAD + NADPH + NADP + H 2 O H + FIGURE 24.12 (1) Elongation of fatty acids in mitochondria is initiated by the thiolase reaction.The ␤-ketoacyl intermediate thus formed undergoes the same three reac- tions (in reverse order) that are the basis of ␤-oxidation of fatty acids. (2) Reduction of the ␤-keto group is followed by (3) dehydration to form a double bond. (4) Reduction of the double bond yields a fatty acyl-CoA that is elon- gated by two carbons. Note that the reducing coenzyme for the second step is NADH, whereas the reductant for the fourth step is NADPH. 734 Chapter 24 Lipid Biosynthesis In E. coli, the biosynthesis of a monounsaturated fatty acid begins with four normal cycles of elongation to form a ten-carbon intermediate, ␤-hydroxydecanoyl-ACP (Fig- ure 24.13). At this point, ␤-hydroxydecanoyl thioester dehydrase forms a double bond ␤,␥ to the thioester and in the cis configuration. This is followed by three rounds of the normal elongation reactions to form palmitoleoyl-ACP. Elongation may terminate at this point or may be followed by additional biosynthetic events. The principal unsaturated fatty acid in E. coli, cis-vaccenic acid, is formed by an additional elongation step, using palmitoleoyl-ACP as a substrate. Unsaturation Reactions Occur in Eukaryotes in the Middle of an Aliphatic Chain The addition of double bonds to fatty acids in eukaryotes does not occur until the fatty acyl chain has reached its full length (usually 16 to 18 carbons). Dehydro- genation of stearoyl-CoA occurs in the middle of the chain, despite the absence of any useful functional group on the chain to facilitate activation: CH 3 O(CH 2 ) 16 COOSCoA ⎯⎯→ CH 3 O(CH 2 ) 7 CHPCH(CH 2 ) 7 COOSCoA This impressive reaction is catalyzed by stearoyl-CoA desaturase, a 53-kD enzyme containing a nonheme iron center. NADH and O 2 are required, as are two other proteins: cytochrome b 5 reductase (a 43-kD flavoprotein) and cytochrome b 5 (16.7 kD). All three proteins are associated with the ER membrane. Cytochrome b 5 reductase transfers a pair of electrons from NADH through FAD to cyto- chrome b 5 (Figure 24.14). Oxidation of reduced cytochrome b 5 is coupled to re- duction of nonheme Fe 3ϩ to Fe 2ϩ in the desaturase. The Fe 3ϩ accepts a pair of electrons (one at a time in a cycle) from cytochrome b 5 and creates a cis double bond at the 9,10-position of the stearoyl-CoA substrate. O 2 is the terminal elec- tron acceptor in this fatty acyl desaturation cycle. Note that two water molecules are made, which means that four electrons are transferred overall. Two of these come through the reaction sequence from NADH, and two come from the fatty acyl substrate that is being dehydrogenated. The Unsaturation Reaction May Be Followed by Chain Elongation Additional chain elongation can occur following this single desaturation reac- tion. The oleoyl-CoA produced can be elongated by two carbons to form a 20Ϻ1 cis -⌬ 11 fatty acyl-CoA. If the starting fatty acid is palmitate, reactions similar to the preceding scheme yield palmitoleoyl-CoA (16Ϻ1 cis-⌬ 9 ), which subsequently can be elongated to yield cis -vaccenic acid (18Ϻ1 cis-⌬ 11 ). Similarly, C 16 and C 18 fatty acids can be elongated to yield C 22 and C 24 fatty acids, such as are often found in sphingolipids. CH 3 (CH 2 ) 5 CH 2 C H OH CH 2 C O S-ACP CH 3 (CH 2 ) 5 H C ␥ CH 2 C O S-ACP H C ␤ H 2 O Acetyl-ACP + 4 Malonyl-ACP Four rounds of fatty acyl synthase ␤-Hydroxydecanoyl–ACP ␤-Hydroxydecanoyl thioester dehydrase Three rounds of fatty acyl synthase Palmitoleoyl-ACP (16:1 Δ9 –ACP) cis-Vaccenoyl-ACP 18:1 Δ11 –ACP Elongation at ER FIGURE 24.13 Double bonds are introduced into the growing fatty acid chain in E. coli by specific dehydrases. Palmitoleoyl-ACP is synthesized by a sequence of reac- tions involving four rounds of chain elongation, fol- lowed by double bond insertion by ␤-hydroxydecanoyl thioester dehydrase and three additional elongation steps. Another elongation cycle produces cis-vaccenic acid. CH 3 (CH 2 ) 7 C (CH 2 ) 7 C S H C H CH 3 (CH 2 ) 16 C O O S CoA CoA Cytochrome b 5 reductase (FAD) 2 Cytochrome b 5 (Fe 3+ ) (Oxidized) H + 2 H + 2 H + O 2 2 H 2 O + Cytochrome b 5 reductase (FADH 2 ) 2 Cytochrome b 5 (Fe 2+ ) (Reduced) Desaturase (Fe 3+ ) Desaturase (Fe 2+ ) + Oleoyl-CoA +Stearoyl-CoA + NAD + NADH FIGURE 24.14 The conversion of stearoyl-CoA to oleoyl-CoA in eukaryotes is catalyzed by stearoyl-CoA desat- urase in a reaction sequence that also involves cytochrome b 5 and cytochrome b 5 reductase.Two electrons are passed from NADH through the chain of reactions as shown, and two electrons are derived from the fatty acyl substrate. 24.1 How Are Fatty Acids Synthesized? 735 Mammals Cannot Synthesize Most Polyunsaturated Fatty Acids Organisms differ with respect to formation, processing, and utilization of polyun- saturated fatty acids. E. coli, for example, does not have any polyunsaturated fatty acids. Eukaryotes do synthesize a variety of polyunsaturated fatty acids, certain or- ganisms more than others. For example, plants manufacture double bonds be- tween the ⌬ 9 and the methyl end of the chain, but mammals cannot. Plants read- ily desaturate oleic acid at the 12-position (to give linoleic acid) or at both the 12- and 15-positions (producing linolenic acid). Mammals require polyunsatu- rated fatty acids but must acquire them in their diet. As such, these fatty acids are referred to as essential fatty acids. On the other hand, mammals can introduce double bonds between the double bond at the 8- or 9-position and the carboxyl group. Enzyme complexes in the ER desaturate the 5-position, provided a double bond exists at the 8-position, and form a double bond at the 6-position if one al- ready exists at the 9-position. Thus, oleate can be unsaturated at the 6,7-position to give an 18Ϻ2 cis -⌬ 6 ,⌬ 9 fatty acid. Arachidonic Acid Is Synthesized from Linoleic Acid by Mammals Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 24.15). This fatty acid is the precursor for prostaglandins and other biologically ac- tive derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl es- ter of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the COO – 12 9 C S O C 12 9 S O 6 C 14 11 S O 8 14 11 8 5 C S O 14 11 8 5 C O O _ + + P P ATP CoA CoA CoA CoA AMP CoA Linoleic acid (18:2 Δ9,12 ) Linoleoyl-CoA (18:2 Δ9,12 –CoA) Linolenoyl-CoA (18:3 Δ6,9,12 –CoA) (20:3 Δ8,11,14 –CoA) Arachidonoyl-CoA (20:4 Δ5,8,11,14 –CoA) Arachidonic acid Acyl-CoA synthetase 2 H 2 H Desaturation Desaturation CO 2 Malonyl-CoA Elongation + CoA H 2 O CoA FIGURE 24.15 Arachidonic acid is synthesized from linoleic acid in eukaryotes.This is the means by which animals synthesize fatty acids with double bonds at positions other than C-9. 736 Chapter 24 Lipid Biosynthesis 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position, followed by a reverse acyl-CoA synthetase reaction (see Chapter 23), liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, 11-, and 14-positions. Regulatory Control of Fatty Acid Metabolism Is an Interplay of Allosteric Modifiers and Phosphorylation–Dephosphorylation Cycles The control and regulation of fatty acid synthesis is intimately related to regulation of fatty acid breakdown, glycolysis, and the TCA cycle. Acetyl-CoA is an important intermediate metabolite in all these processes. In these terms, it is easy to appreci- ate the interlocking relationships in Figure 24.16. Malonyl-CoA can act to prevent fatty acyl-CoA derivatives from entering the mitochondria by inhibiting the carni- tine acyltransferase of the outer mitochondrial membrane that initiates this trans- port. In this way, when fatty acid synthesis is turned on (as signaled by higher lev- els of malonyl-CoA), ␤-oxidation is inhibited. As we pointed out earlier, citrate is an important allosteric activator of acetyl-CoA carboxylase, and fatty acyl-CoAs are inhibitors. The degree of inhibition is proportional to the chain length of the fatty acyl-CoA; longer chains show a higher affinity for the allosteric inhibition site on acetyl-CoA carboxylase. Palmitoyl-CoA, stearoyl-CoA, and arachidyl-CoA are the most potent inhibitors of the carboxylase. HUMAN BIOCHEMISTRY ␻3 and ␻6—Essential Fatty Acids with Many Functions Linoleic acid and ␣-linolenic acid are termed essential fatty acids be- cause animals cannot synthesize them and must acquire them in their diet. Linoleic acid is the precursor of arachidonic acid, and both of these are referred to as ␻6 fatty acids because, counting from the end (omega, ␻) carbon of the chain, the first double bond is at the sixth position (see figure). Similarly, ␣-linolenic acid is the precursor of eicosapentaenoic acid and docosahexaenoic acid (DHA), and these three are termed ␻3 fatty acids. Vegetable oils are rich in linoleic acid and thus satisfy the body’s ␻6 dietary requirements, whereas fish oils (for example, cod, herring, men- haden, and salmon) are rich in ␻3 fatty acids. The ω6 fatty acids are precursors of prostaglandins, thrombox- anes, and leukotrienes (see Section 24.3). The ␻3 fatty acids have beneficial effects in a variety of organs and biological processes, in- cluding growth regulation, platelet activation, and lipoprotein metabolism. The ␻3 fats are generally cardioprotective, anti- inflammatory, and anticarcinogenic. Interestingly, especially high levels of DHA have been found in rod cell membranes in animal retina and in neural tissue. DHA is approximately 22% of total fatty acids in animal retina and 35% to 40% of the fatty acids in retinal phosphatidylethanolamine. DHA supports neural and visual development, in part because it is a pre- cursor for eicosanoids that regulate numerous cell and organ func- tions. Infants can synthesize DHA and other polyunsaturated fatty acids, but the rates of synthesis are low. Strong evidence exists for the importance of these fatty acids in infant nutrition. COOH COOH COOH ␻6 Essential fatty acid ␻3 Essential fatty acid COOH COOH Linoleic acid (18:2 ␻6) ␣-Linoleic acid (18:3 ␻3) Arachidonic acid (20:4 ␻6) Eicosapentaenoic acid (EPA; 20:5 ␻3) Docosahexaenoic acid (DHA; 22:6 ␻3) ᮣ The “␻” numbering system, where the position of the first double bond relative to the methyl (␻) group is indi- cated (red box), is useful because the ␻ double bond posi- tion is retained during chain elongation and desaturation. 24.2 How Are Complex Lipids Synthesized? 737 Hormonal Signals Regulate ACC and Fatty Acid Biosynthesis As described earlier, citrate activation and palmitoyl-CoA inhibition of acetyl-CoA carboxylase are strongly dependent on the phosphorylation state of the enzyme. This provides a crucial connection to hormonal regulation. Many of the enzymes that act to phosphorylate acetyl-CoA carboxylase (see Figure 24.4) are controlled by hormonal signals. Glucagon is a good example (Figure 24.17). As noted in Chapter 22, glucagon binding to membrane receptors activates an intracellular cascade in- volving activation of adenylyl cyclase. Cyclic AMP produced by the cyclase activates a protein kinase, which then phosphorylates acetyl-CoA carboxylase. Unless citrate levels are high, phosphorylation causes inhibition of fatty acid biosynthesis. The car- boxylase (and fatty acid synthesis) can be reactivated by a specific phosphatase, which dephosphorylates the carboxylase. Also indicated in Figure 24.17 is the simultaneous activation by glucagon of triacylglycerol lipases, which hydrolyze tri- acylglycerols, releasing fatty acids for ␤-oxidation. Both the inactivation of acetyl- CoA carboxylase and the activation of triacylglycerol lipase are counteracted by insulin, whose receptor acts to stimulate a phosphodiesterase that converts cAMP to AMP. 24.2 How Are Complex Lipids Synthesized? Complex lipids consist of backbone structures to which fatty acids are covalently bound. Principal classes include the glycerolipids, for which glycerol is the back- bone, and sphingolipids, which are built on a sphingosine backbone. The two major classes of glycerolipids are glycerophospholipids and triacylglycerols. The phospholipids, which include both glycerophospholipids and sphingomyelins, are crucial components of membrane structure. They are also precursors of hormones such as the eicosanoids (for example, prostaglandins) and signal molecules (such as the breakdown products of phosphatidylinositol). Different organisms possess greatly different complements of lipids and therefore invoke somewhat different lipid biosynthetic pathways. For example, sphingolipids + Acetyl-CoA Citric acid cycle Malate Oxaloacetate Oxaloacetate Fatty acyl-CoA ␤-Oxidation Citrate Acetyl-CoA Malonyl-CoA Acetyl-CoA carboxylase Fatty acyl-CoA Fatty acid Triacylglycerol Carnitine Carnitine acyltransferase-1 Citrate Glucose 2 Pyruvate FIGURE 24.16 Regulation of fatty acid synthesis and fatty acid oxidation are coupled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria.When fatty acyl-CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abun- dance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 738 Chapter 24 Lipid Biosynthesis and triacylglycerols are produced only in eukaryotes. In contrast, bacteria usually have rather simple lipid compositions. Phosphatidylethanolamine accounts for at least 75% of the phospholipids in E. coli, with phosphatidylglycerol and cardi- olipin accounting for most of the rest. E. coli membranes possess no phosphatidyl- choline, phosphatidylinositol, sphingolipids, or cholesterol. On the other hand, some bacteria (such as Pseudomonas) can synthesize phosphatidylcholine, for exam- ple. In this section and the one following, we consider some of the pathways for the synthesis of glycerolipids, sphingolipids, and the eicosanoids, which are derived from phospholipids. Glycerolipids Are Synthesized by Phosphorylation and Acylation of Glycerol A common pathway operates in nearly all organisms for the synthesis of phospha- tidic acid, the precursor to other glycerolipids. Glycerokinase catalyzes the phos- phorylation of glycerol to form glycerol-3-phosphate, which is then acylated at both the 1- and 2-positions to yield phosphatidic acid (Figure 24.18). The first acylation, at position 1, is catalyzed by glycerol-3-phosphate acyltransferase, an enzyme that in most organisms is specific for saturated fatty acyl groups. Eukaryotic systems can also utilize dihydroxyacetone phosphate as a starting point for synthesis of phos- phatidic acid (Figure 24.18). Again a specific acyltransferase adds the first acyl chain, followed by reduction of the backbone keto group by acyldihydroxyacetone phosphate Glucagon receptor Adenylyl cyclase Insulin receptor Dephospho-acetyl-CoA carboxylase (Active at low [citrate]) Phosphatases Phospho-acetyl-CoA carboxylase (Active only at high [citrate]) PPPPP P P P cAMP Phosphodiesterase Glucagon G protein Insulin Protein kinase (inactive) Protein kinase (active) Triacylglycerol lipase (active) Triacylglycerol lipase (inactive) Triacylglycerols Fatty acids and glycerol HPO 4 2 _ Phosphatases HPO 4 2 _ ATP ATP ADPH 2 O H 2 O ATP ADP AMP FIGURE 24.17 Hormonal signals regulate fatty acid syn- thesis, primarily through actions on acetyl-CoA carboxy- lase. Availability of fatty acids also depends upon hor- monal activation of triacylglycerol lipase. 24.2 How Are Complex Lipids Synthesized? 739 reductase, using NADPH as the reductant. Alternatively, dihydroxyacetone phosphate can be reduced to glycerol-3-phosphate by glycerol-3-phosphate dehydrogenase. Eukaryotes Synthesize Glycerolipids from CDP-Diacylglycerol or Diacylglycerol In eukaryotes, phosphatidic acid is converted directly either to diacylglycerol or to cytidine diphosphodiacylglycerol (or simply CDP-diacylglycerol; Figure 24.19). From these two precursors, all other glycerophospholipids in eukaryotes are derived. Diacylglyc- erol is a precursor for synthesis of triacylglycerol, phosphatidylethanolamine, and C C CH 2 CH 2 OH O – O P O – O O H Glycerol-3-P Glycerol R 1 C O S-ACP CoA or ACP HO C CH 2 OH CH 2 OH HHO C CH 2 CH 2 O – O P O – O HHO OC O R 1 C O R 1 C O R 2 C O or S-ACP C CH 2 CH 2 O – O P O – O HO O C O R 2 CoASH or ACP-SH C C CH 2 CH 2 OH O – O P O – O O O C O R 1 CH 2 CH 2 O – O P O – O OC O R 1 + + NADP + NADPH H + H + NAD + NADH SCoA SCoA CoA ATP ADP R 2 or SCoA R 1 1-Acylglycerol-3-P Glycerol-3-P acyltransferase Glycerol-3-P dehydrogenase 1-Acylglycerol-3-P acyltransferase Phosphatidic acid Glycerokinase Dihydroxyacetone-P 1-Acyldihydroxyacetone-P Dihydroxyacetone-P acyltransferase Acyldihydroxyacetone-P reductase FIGURE 24.18 Synthesis of glycerolipids in eukaryotes begins with the formation of phosphatidic acid, which may be formed from dihydroxyacetone phosphate or glycerol as shown. 740 Chapter 24 Lipid Biosynthesis phosphatidylcholine. Triacylglycerol is synthesized mainly in adipose tissue, liver, and intestines and serves as the principal energy storage molecule in eukaryotes. Triacyl- glycerol biosynthesis in liver and adipose tissue occurs via diacylglycerol acyltrans- ferase, an enzyme bound to the cytoplasmic face of the ER. A different route is used, however, in intestines. Recall (see Figure 23.3) that triacylglycerols from the diet are CH 2 HOCH 2 CH 2 NH 3 OCH 2 CH 2 NH 3 – O P O – O + + OCH 2 CH 2 NH 3 O – P O O + P O – O O Cytidine OCH 2 CH 2 NH 3 O – P O O + O C O R 2 CH 2 OC O R 1 CH 2 OH O C O R 2 CH 2 OC O R 1 Diacylglycerol C O R 3 SCoA C H O C O R 2 CH 2 OC O R 1 CH 2 O C O R 3 OC O R 2 CH 2 OC O R 1 CH 2 O OCH 2 CH 2 N(CH 3 ) 3 O – P O + O – P O OP O – O O Cytidine OCH 2 CH 2 N(CH 3 ) 3 + – O P O – O OCH 2 CH 2 N(CH 3 ) 3 + HOCH 2 CH 2 N(CH 3 ) 3 + Phosphatidic acid CH 2 O C O R 2 CH 2 O C O R 1 O O – P O O – P P P P P CH CH CH CH P P CTP CH 2 R 1 CH CH 2 O C O R 2 O P C O O O P O Cytidine O – O O – O ATP ATP ATP Ethanolamine Ethanolamine kinase Phosphoethanolamine CTP: Phospho- ethanolamine cytidylyltransferase CDP-ethanolamine Phosphatidylethanolamine CoASH Diacylglycerol acyltransferase Triacylglycerol Phosphatidylcholine CDP-ethanolamine: 1,2- diacylglycerol phospho- ethanolamine transferase CMP CDP-choline CDP-choline: 1,2-diacylgly- cerol phospho- choline transferase Choline Choline kinase Phosphocholine CTP: Phosphocholine cytidylyltransferase Phosphatidic acid phosphatase Diacylglycerol kinase CTP CTP CMP Phosphatidate cytidylyltransferase CDP-diacylglycerol ADP H 2 O ADP ADP FIGURE 24.19 Diacylglycerol and CDP-diacylglycerol are the principal precursors of glycerolipids in eukaryotes. Phosphatidylethanolamine and phosphatidylcholine are formed by reaction of diacylglycerol with CDP- ethanolamine or CDP-choline, respectively. 24.2 How Are Complex Lipids Synthesized? 741 broken down to 2-monoacylglycerols by specific lipases. Acyltransferases then acylate 2-monoacylglycerol to produce new triacylglycerols (Figure 24.20). Phosphatidylethanolamine Is Synthesized from Diacylglycerol and CDP-Ethanolamine Phosphatidylethanolamine synthesis begins with phosphorylation of ethanolamine to form phosphoethanolamine (see Figure 24.19). The next reaction involves trans- fer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP i hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Bio- synthesis of phosphatidylcholine is entirely analogous because animals can synthe- size it directly. All of the choline utilized in this pathway must be acquired from the diet. On the other hand, yeast, certain bacteria, and animal livers can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involv- ing S -adenosylmethionine (see Chapter 25). Exchange of Ethanolamine for Serine Converts Phosphatidylethanolamine to Phosphatidylserine Mammals synthesize phosphatidylserine (PS) in a calcium ion–dependent reaction involving aminoalcohol exchange (Figure 24.21). The enzyme catalyzing this reaction is associated with the ER and will accept phosphatidylethanolamine (PE) and other phospholipid substrates. A mitochondrial PS decarboxylase can subsequently convert PS to PE. No other pathway converting serine to ethanolamine has been found. Eukaryotes Synthesize Other Phospholipids Via CDP-Diacylglycerol Eukaryotes also use CDP-diacylglycerol, derived from phosphatidic acid, as a precur- sor for several other important phospholipids, including phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin (Figure 24.22). PI accounts for only about OC O R 2 C CH 2 OH CH 2 OH C O R 1 S CH CH 2 CH 2 OH OC O R 1 CR 3 O C O R 2 C O R 2 CH CH 2 O O O C O R 1 CH 2 OC O R 3 H S CoA CoA 2-Monoacylglycerol Monoacylglycerol acyltransferase Diacylglycerol Diacylglycerol acyltransferase Triacylglycerol Lipases Dietary triacylglycerols CoASH CoASH FIGURE 24.20 Triacylglycerols are formed primarily by the action of acyltransferases on monoacylglycerol and diacylglycerol. OCH 2 CH O C O R 2 CH 2 OC O R 1 O O – O – P O CH 2 CH 2 NH 3 + OCH 2 CH O C O R 2 CH 2 OC O R 1 O P O CH 2 C H COO – NH 3 + Phosphatidylethanolamine SerineSerine CO 2 EthanolamineEthanolamine Base exchange enzyme (endoplasmic reticulum) Phosphatidylserine decarboxylase (mitochondria) Phosphatidylserine Serine FIGURE 24.21 The interconversion of phosphatidylethanolamine and phosphatidylserine in mammals. 742 Chapter 24 Lipid Biosynthesis CC CH 2 CH 2 O P O – O R 2 HO CR 1 O O O P O – O CH 2 O OH OH O N N NH 2 CC CH 2 O R 2 HO H CH 2 OH CH 2 O POC O – O – CC CH 2 O P O – O O R 2 HO O O P O – O O CH 2 C OH CH 2 OH H Glycerol CDP-diacylglycerol CC CH 2 O P O – O O R 2 HO O CH 2 C OH CH 2 H O P O – O O CH 2 C O C O O C O O O CH 2 CR 1 O O CC CH 2 O R 2 HO O O PO – O OH OH OH H H H H OH HO CH 2 CR 1 O O CH 2 CR 1 O O CH 2 CH 2 CR 1 O O H H H CDP-diacylglycerol CMP CMP Glycerol-3-PInositol Glycerophosphate phosphatidyltransferase Phosphatidylinositol synthase Phosphoglycerol Phosphatidylglycerol-P P i Phosphatidylinositol Phosphatidylglycerol-P phosphatase Phosphatidylglycerol CMP Cardiolipin synthase Glycerol Cardiolipin R 1 Ј R 2 Ј FIGURE 24.22 CDP-diacylglycerol is a precursor of phosphatidylinositol, phosphatidylglycerol, and cardiolipin in eukaryotes.