1020 CHAPTER TWENTY-SIX Lipids PROBLEM 26.2 Using HSCoA and Hs-ACP as abbreviations for coenzyme a and acyl carrier protein, respectively, write a structural formula for the tetrahedral intermediate in the preceding reaction A second molecule of acetyl coenzyme A reacts with carbon dioxide(actually bicarbonate ion at biological pH) to give malonyl coenzyme A CH3 CSCoA HCO3 OCCH, CSCoA HO Malony Water coenzyme A coenzyme A Formation of malonyl coenzyme A is followed by a nucleophilic acyl substitution, which transfers the malonyl group to the acyl carrier protein as a thioester. OCCHCSCOA+HS一ACP OCCHCS-ACP+ HSCOA Acyl carrier S-Malonyl acyl When both building block units are in place on the acyl carrier protein, carbon-car- bon bond formation occurs between the a-carbon atom of the malonyl group and the carbonyl carbon of the acetyl group. This is shown in step I of Figure 26.3. Carbon-car- bon bond formation is accompanied by decarboxylation and produces a four-carbon ace- toacetyl (3-oxobutanoyl) group bound to acyl carrier protein. The acetoacetyl group is then transformed to a butanoyl group by the reaction equence illustrated in steps 2 to 4 of Figure 26.3. The four carbon atoms of the butanoyl group originate in two molecules of acetyl coenzyme A. Carbon dioxide assists the reaction but is not incorporated into the prod uct. The same carbon dioxide that is used to convert one molecule of acetyl coenzyme A to malonyl coenzyme A is regenerated in the decarboxylation step that accompanies carbon-carbon bond formation Successive repetitions of the steps shown in Figure 26.3 give unbranched acyl groups having 6, 8, 10, 12, 14, and 16 carbon atoms. In each case, chain extension occurs by reaction with a malonyl group bound to the acyl carrier protein. Thus, the biosyn- thesis of the 16-carbon acyl group of hexadecanoic (palmitic) acid can be represented by the overall equation oO CH3CS-ACP 7HOCCH, CS-ACP+ 14 NADPH 14 H3o S-Malonyl acyl Reduced form Hydronium carner protein carrier protein of coenzyme CH3(CH2)14CS-ACP+ 7C0,+ 7HS-ACP+ 14 NADP 21 H,O S-Hexadecanoyl acyl Carbon Acyl carrier Oxidized form Water dioxide of Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
1020 CHAPTER TWENTY-SIX Lipids PROBLEM 26.2 Using HSCoA and HS±ACP as abbreviations for coenzyme A and acyl carrier protein, respectively, write a structural formula for the tetrahedral intermediate in the preceding reaction. A second molecule of acetyl coenzyme A reacts with carbon dioxide (actually bicarbonate ion at biological pH) to give malonyl coenzyme A: Formation of malonyl coenzyme A is followed by a nucleophilic acyl substitution, which transfers the malonyl group to the acyl carrier protein as a thioester. When both building block units are in place on the acyl carrier protein, carbon–carbon bond formation occurs between the -carbon atom of the malonyl group and the carbonyl carbon of the acetyl group. This is shown in step 1 of Figure 26.3. Carbon–carbon bond formation is accompanied by decarboxylation and produces a four-carbon acetoacetyl (3-oxobutanoyl) group bound to acyl carrier protein. The acetoacetyl group is then transformed to a butanoyl group by the reaction sequence illustrated in steps 2 to 4 of Figure 26.3. The four carbon atoms of the butanoyl group originate in two molecules of acetyl coenzyme A. Carbon dioxide assists the reaction but is not incorporated into the product. The same carbon dioxide that is used to convert one molecule of acetyl coenzyme A to malonyl coenzyme A is regenerated in the decarboxylation step that accompanies carbon–carbon bond formation. Successive repetitions of the steps shown in Figure 26.3 give unbranched acyl groups having 6, 8, 10, 12, 14, and 16 carbon atoms. In each case, chain extension occurs by reaction with a malonyl group bound to the acyl carrier protein. Thus, the biosynthesis of the 16-carbon acyl group of hexadecanoic (palmitic) acid can be represented by the overall equation: 7HS ACP Acyl carrier protein 21 H2O Water 14 NADP Oxidized form of coenzyme 7CO2 Carbon dioxide S-Hexadecanoyl acyl carrier protein ACP O CH3(CH2)14CS 14 NADPH Reduced form of coenzyme 14 H3O Hydronium ion S-Acetyl acyl carrier protein ACP O CH3CS S-Malonyl acyl carrier protein ACP O 7HOCCH2CS O HS ACP Acyl carrier protein O O OCCH2CSCoA Malonyl coenzyme A HSCoA Coenzyme A S-Malonyl acyl carrier protein ACP O O OCCH2CS O CH3CSCoA Acetyl coenzyme A O O OCCH2CSCoA Malonyl coenzyme A H2O Water HCO3 Bicarbonate Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
26.3 Fatty Acid Biosynthesis 1021 Step 1: An acetyl group is transferred to the a carbon atom of the malonyl group with evolution of carbon dioxide. Presumably decarboxylation gives an enol, which attacks the acetyl group ACP -O-C=0 CH C-CH, CS- ACP +-S-ACP C-CH CS-ACP Acetyl and malonyl groups bound to acyl acyl carrier Step 2: The ketone carbonyl of the acetoacetyl group is reduced to an alcohol function. This reduction requires NADPH as a coenzyme (NADPH is the phosphate ester of NADh and reacts similarly to it. CH CCH CS-ACP NADPh+ HO+ CH,CHCH,CS-ACP NADP+ H,O Reduced Hydronium Oxidized form of acyl carrier protein form of coenzyme Step 3: Dehydration of the B-hydroxy acyl group CH CHCH CS-ACP CHCH=CHCS一ACP+H2O S-ci carey brtateiy acyl carrier protein Step 4: Reduction of the double bond of the a, B-unsaturated acyl group. This step requires NADPH as a coenzyme CH ACP NADPH HO+ > CH CH-CH CS -ACP+ NADP++ Ho S-2-Butenoyl Reduced Hydronium S-Butanoyl Oxidized coenzym 26.3 Mechanism of PROBLEM 26.3 By analogy to the intermediates given in steps 1-4 of Figure hesis of a butanoyl 26.3, write the sequence of acyl groups that are attached to the acyl carrier pro- rom acetyl and mal tein in the conversion of onyl building blocks CH3(CH2)12CS-ACP to CH3(CH2)14CS-ACP Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
26.3 Fatty Acid Biosynthesis 1021 PROBLEM 26.3 By analogy to the intermediates given in steps 1–4 of Figure 26.3, write the sequence of acyl groups that are attached to the acyl carrier protein in the conversion of CH3(CH2)12CS±ACP to O X CH3(CH2)14CS±ACP O X Step 1: An acetyl group is transferred to the carbon atom of the malonyl group with evolution of carbon dioxide. Presumably decarboxylation gives an enol, which attacks the acetyl group. Step 2: The ketone carbonyl of the acetoacetyl group is reduced to an alcohol function. This reduction requires NADPH as a coenzyme. (NADPH is the phosphate ester of NADH and reacts similarly to it.) CH3C O S ACP O O C CH2CS O ACP Acetyl and malonyl groups bound to acyl carrier protein O C O CH3C O CH2CS O ACP S ACP Carbon dioxide S-Acetoacetyl acyl carrier protein Acyl carrier protein (anionic form) CH3CCH O 2CS O ACP S-Acetoacetyl acyl carrier protein NADPH Reduced form of coenzyme H3O Hydronium ion CH3CHCH2CS O ACP S-3-Hydroxybutanoyl acyl carrier protein NADP Oxidized form of coenzyme H2O Water OH Step 3: Dehydration of the -hydroxy acyl group. CH3CHCH2CS O ACP S-3-Hydroxybutanoyl acyl carrier protein OH CH3CH CHCS O ACP S-2-Butenoyl acyl carrier protein H2O Water Step 4: Reduction of the double bond of the , -unsaturated acyl group. This step requires NADPH as a coenzyme. CH3CH CHCS O ACP S-2-Butenoyl acyl carrier protein NADPH Reduced form of coenzyme H3O Hydronium ion CH3CH CH2CS O ACP S-Butanoyl acyl carrier protein NADP Oxidized form of coenzyme H2O Water 2 FIGURE 26.3 Mechanism of biosynthesis of a butanoyl group from acetyl and malonyl building blocks. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-SIX Lipids This phase of fatty acid biosynthesis concludes with the transfer of the acyl group from acyl carrier protein to coenzyme A. The resulting acyl coenzyme a molecules car then undergo a number of subsequent biological transformations. One such transforma tion is chain extension, leading to acyl groups with more than 16 carbons. Another is the introduction of one or more carbon-carbon double bonds. A third is acyl transfer from sulfur to oxygen to form esters such as triacylglycerols. The process by which acyl coenzyme A molecules are converted to triacylglycerols involves a type of intermediate alled a phospholipid and is discussed in the following section 26. 4 PHOSPHOLIPIDS Triacylglycerols arise, not by acylation of glycerol itself, but by a sequence of steps in which the first stage is acyl transfer to L-glycerol 3-phosphate(from reduction of dihy droxyacetone 3-phosphate, formed as described in Section 25. 21). The product of this stage is called a phosphatidic acid. CH,OH O o CH,OCR H RCSCoA +R'cSCoa RCO H 2HSCOA CH,,H CH,OPO3H2 Glycer Two acyl coenzyme a molecules Phosphated Coenzyme a 3- (R and r may be the same or they may be different PROBLEM 26.4 What is the absolute configuration(R or S)of L-glycerol 3- phosphate? What must be the absolute configuration of the naturally occurring phosphatidic acids biosynthesized from it? Hydrolysis of the phosphate ester function of the phosphatidic acid gives a diacylglycerol, which then reacts with a third acyl coenzyme A molecule to produce a triacylglycerol O CH,OCR O CH,OCR O CHOCR RCO >RCO R CSCOA H →RCO+H CH,OPO3H2 CHOH CH,OCR Phosphatidic acid Diacylglycerol Triacylglycerol Phosphatidic acids not only are intermediates in the biosynthesis of triacylglycerols but also are biosynthetic precursors of other members of a group of compounds called phosphoglycerides or glycerol phosphatides. Phosphorus-containing derivatives of lipids are known as phospholipids, and phosphoglycerides are one type of phospholipid. nt to prevent One important phospholipid is phosphatidylcholine, also called lecithin. Phos- from sepa- phatidylcholine is a mixture of diesters of phosphoric acid. One ester function is derived from a diacylglycerol, whereas the other is a choline [-OCH2CH2N(CH3)3) unit Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
1022 CHAPTER TWENTY-SIX Lipids This phase of fatty acid biosynthesis concludes with the transfer of the acyl group from acyl carrier protein to coenzyme A. The resulting acyl coenzyme A molecules can then undergo a number of subsequent biological transformations. One such transformation is chain extension, leading to acyl groups with more than 16 carbons. Another is the introduction of one or more carbon–carbon double bonds. A third is acyl transfer from sulfur to oxygen to form esters such as triacylglycerols. The process by which acyl coenzyme A molecules are converted to triacylglycerols involves a type of intermediate called a phospholipid and is discussed in the following section. 26.4 PHOSPHOLIPIDS Triacylglycerols arise, not by acylation of glycerol itself, but by a sequence of steps in which the first stage is acyl transfer to L-glycerol 3-phosphate (from reduction of dihydroxyacetone 3-phosphate, formed as described in Section 25.21). The product of this stage is called a phosphatidic acid. PROBLEM 26.4 What is the absolute configuration (R or S) of L-glycerol 3- phosphate? What must be the absolute configuration of the naturally occurring phosphatidic acids biosynthesized from it? Hydrolysis of the phosphate ester function of the phosphatidic acid gives a diacylglycerol, which then reacts with a third acyl coenzyme A molecule to produce a triacylglycerol. Phosphatidic acids not only are intermediates in the biosynthesis of triacylglycerols but also are biosynthetic precursors of other members of a group of compounds called phosphoglycerides or glycerol phosphatides. Phosphorus-containing derivatives of lipids are known as phospholipids, and phosphoglycerides are one type of phospholipid. One important phospholipid is phosphatidylcholine, also called lecithin. Phosphatidylcholine is a mixture of diesters of phosphoric acid. One ester function is derived from a diacylglycerol, whereas the other is a choline unit. [±OCH2CH2N(CH3)3] H O RCO CH2OPO3H2 CH2OCR O Phosphatidic acid H O RCO CH2OH CH2OCR O Diacylglycerol H O RCO CH2OCR CH2OCR O O Triacylglycerol H2O RCSCoA O X Lecithin is added to foods such as mayonnaise as an emulsifying agent to prevent the fat and water from separating into two layers. HO H CH2OPO3H2 CH2OH L-Glycerol 3-phosphate O RCSCoA O RCSCoA Two acyl coenzyme A molecules (R and R may be the same or they may be different) H O RCO CH2OPO3H2 CH2OCR O Phosphatidic acid 2HSCoA Coenzyme A Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
26.4 Phospholipids o CHOCK H CH,OPO OCH,CH,N(CH3)3 Phosphatidylcholine (R and rare usually Phosphatidylcholine possesses a polar"head group"(the positively charged choline and negatively charged phosphate units) and two nonpolar""tails"(the acyl groups) Under certain conditions, such as at the interface of two aqueous phases, phosphatidyl- choline forms what is called a lipid bilayer, as shown in Figure 26.4. Because there are two long-chain acyl groups in each molecule, the most stable assembly has the polar groups solvated by water molecules at the top and bottom surfaces and the lipophilic acyl groups directed toward the interior of the bilayer. Phosphatidylcholine is one of the principal components of cell membranes. These membranes are composed of lipid bilayers analogous to those of Figure 26. 4. Nonpola materials can diffuse through the bilayer from one side to the other relatively easily; polar materials, particularly metal ions such as Na, K, and Ca*+, cannot. The transport of metal ions through a membrane is usually assisted by certain proteins present in the lipid bilayer, which contain a metal ion binding site surrounded by a lipophilic exterior. The metal ion is picked up at one side of the lipid bilayer and delivered at the other, sur- rounded at all times by a polar environment on its passage through the hydrocarbon-like interior of the membrane lonophore antibiotics such as monensin(Section 16. 4)disrupt the normal functioning of cells by facilitating metal ion transport across cell membranes Hydrophilic 88888 Hydrophilic head groups FIGURE 26.4 Cross section of a phospholipid bilayer. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
26.4 Phospholipids 1023 Phosphatidylcholine possesses a polar “head group” (the positively charged choline and negatively charged phosphate units) and two nonpolar “tails” (the acyl groups). Under certain conditions, such as at the interface of two aqueous phases, phosphatidylcholine forms what is called a lipid bilayer, as shown in Figure 26.4. Because there are two long-chain acyl groups in each molecule, the most stable assembly has the polar groups solvated by water molecules at the top and bottom surfaces and the lipophilic acyl groups directed toward the interior of the bilayer. Phosphatidylcholine is one of the principal components of cell membranes. These membranes are composed of lipid bilayers analogous to those of Figure 26.4. Nonpolar materials can diffuse through the bilayer from one side to the other relatively easily; polar materials, particularly metal ions such as Na, K, and Ca2, cannot. The transport of metal ions through a membrane is usually assisted by certain proteins present in the lipid bilayer, which contain a metal ion binding site surrounded by a lipophilic exterior. The metal ion is picked up at one side of the lipid bilayer and delivered at the other, surrounded at all times by a polar environment on its passage through the hydrocarbon-like interior of the membrane. Ionophore antibiotics such as monensin (Section 16.4) disrupt the normal functioning of cells by facilitating metal ion transport across cell membranes. H O RCO CH2OPO2 CH2OCR O OCH2CH2N(CH3)3 Phosphatidylcholine (R and R are usually different) Water Water Hydrophilic head groups Hydrophilic head groups Lipophilic tails Lipophilic tails FIGURE 26.4 Cross section of a phospholipid bilayer. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
1024 CHAPTER TWENTY-SIX Lipids 26.5 WAXES Waxes are water-repelling solids that are part of the protective coatings of a number of living things, including the leaves of plants, the fur of animals, and the feathers of birds hey are usually mixtures of esters in which both the alkyl and acyl group are unbranched and contain a dozen or more carbon atoms. Beeswax, for example, contains the ester triacontyl hexadecanoate as one component of a complex mixture of hydrocar- bons. alcohols. and esters CH3(CH2)14COCH,(CH2)28CH3 Triacontyl hexadecanoate PROBLEM 26.5 Spermaceti is a wax obtained from the sperm whale. It contains among other materials, an ester known as cetyl palmitate, which is used as an emollient in a number of soaps and cosmetics. The systematic name for cetyl palmitate is hexadecyl hexadecanoate. Write a structural formula for this sub- Fatty acids normally occur naturally as esters; fats, oils, phospholipids, and waxes all are unique types of fatty acid esters. There is, however, an important class of fatty acid derivatives that exists and carries out its biological role in the form of the free acid This class of fatty acid derivatives is described in the following section 26.6 PROSTAGLANDINS Research in physiology carried out in the 1930s established that the lipid fraction of emen contains small amounts of substances that exert powerful effects on smooth mus- cle. Sheep prostate glands proved to be a convenient source of this material and yielded a mixture of structurally related substances referred to collectively as prostaglandins. We now know that prostaglandins are present in almost all animal tissues, where they carry out a variety of regulatory functions Prostaglandins are extremely potent substances and exert their physiological effects at very small concentrations. Because of this, their isolation was difficult, and it was not until 1960 that the first members of this class, designated PGE and PGFla(Figure 26.5), were obtained as pure compounds. More than a dozen structurally related prostaglandins have since been isolated and identified. All the prostaglandins are 20-carbon carboxylic acids and contain a cyclopentane ring. All have hydroxyl groups at C-ll and C-15(for the numbering of the positions in prostaglandins, see Figure 26.5). Prostaglandins belong ing to the F series have an additional hydroxyl group at C-9, and a carbonyl function is COOH COOH CH FIGURE 26.5 Struc HO tures of two representative Prostaglandin el Prostaglandin Fla bering scheme is illustrated PGEj (PGFla) in the structure of PGE1 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
1024 CHAPTER TWENTY-SIX Lipids 26.5 WAXES Waxes are water-repelling solids that are part of the protective coatings of a number of living things, including the leaves of plants, the fur of animals, and the feathers of birds. They are usually mixtures of esters in which both the alkyl and acyl group are unbranched and contain a dozen or more carbon atoms. Beeswax, for example, contains the ester triacontyl hexadecanoate as one component of a complex mixture of hydrocarbons, alcohols, and esters. PROBLEM 26.5 Spermaceti is a wax obtained from the sperm whale. It contains, among other materials, an ester known as cetyl palmitate, which is used as an emollient in a number of soaps and cosmetics. The systematic name for cetyl palmitate is hexadecyl hexadecanoate. Write a structural formula for this substance. Fatty acids normally occur naturally as esters; fats, oils, phospholipids, and waxes all are unique types of fatty acid esters. There is, however, an important class of fatty acid derivatives that exists and carries out its biological role in the form of the free acid. This class of fatty acid derivatives is described in the following section. 26.6 PROSTAGLANDINS Research in physiology carried out in the 1930s established that the lipid fraction of semen contains small amounts of substances that exert powerful effects on smooth muscle. Sheep prostate glands proved to be a convenient source of this material and yielded a mixture of structurally related substances referred to collectively as prostaglandins. We now know that prostaglandins are present in almost all animal tissues, where they carry out a variety of regulatory functions. Prostaglandins are extremely potent substances and exert their physiological effects at very small concentrations. Because of this, their isolation was difficult, and it was not until 1960 that the first members of this class, designated PGE1 and PGF1 (Figure 26.5), were obtained as pure compounds. More than a dozen structurally related prostaglandins have since been isolated and identified. All the prostaglandins are 20-carbon carboxylic acids and contain a cyclopentane ring. All have hydroxyl groups at C-11 and C-15 (for the numbering of the positions in prostaglandins, see Figure 26.5). Prostaglandins belonging to the F series have an additional hydroxyl group at C-9, and a carbonyl function is O CH3(CH2)14COCH2(CH2)28CH3 Triacontyl hexadecanoate O HO CH3 COOH Prostaglandin E1 (PGE1) HO HO Prostaglandin F1 (PGF1) HO 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 CH3 COOH HO FIGURE 26.5 Structures of two representative prosta-glandins. The numbering scheme is illustrated in the structure of PGE1. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website