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CHAPTER 21 Lipid Biosynthesis

Faraday
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CHAPTER 21 Lipid Biosynthesis

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    1. CHAPTER 21 Lipid Biosynthesis Biosynthesis of fatty acids and eicosanoids

    2. ‘Forehead to forehead I meet thee, this third time, Moby Dick!’ [Ahab (Melville, 1851)] Head-butting during male–male aggression is a basal behavior for cetaceans Sinking of Essex (238 ton ship) in 1821 is the first documented case of a sperm whale deliberately striking a ship (Chase, 1821). http://jeb.biologists.org/cgi/content/full/205/12/1755 ‘Forehead to forehead I meet thee, this third time, Moby Dick!’ [Ahab (Melville, 1851)] Head-butting during male–male aggression is a basal behavior for cetaceans Sinking of Essex (238 ton ship) in 1821 is the first documented case of a sperm whale deliberately striking a ship (Chase, 1821). http://jeb.biologists.org/cgi/content/full/205/12/1755

    3. Catabolism and Anabolic of Fatty Acids Proceed via Different Pathways Catabolism of fatty acids produced acetyl-CoA reducing power to NADH location: mitochondria

    4. FIGURE 21-1 (part 1) The acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase has three functional regions: biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction (see Figure 16-16); and transcarboxylase, which transfers activated CO2 (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site. The active enzyme in each step is shaded blue.FIGURE 21-1 (part 1) The acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase has three functional regions: biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction (see Figure 16-16); and transcarboxylase, which transfers activated CO2 (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site. The active enzyme in each step is shaded blue.

    5. FIGURE 21-1 The acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase has three functional regions: biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction (see Figure 16-16); and transcarboxylase, which transfers activated CO2 (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site. The active enzyme in each step is shaded blue.FIGURE 21-1 The acetyl-CoA carboxylase reaction. Acetyl-CoA carboxylase has three functional regions: biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction (see Figure 16-16); and transcarboxylase, which transfers activated CO2 (shaded green) from biotin to acetyl-CoA, producing malonyl-CoA. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site. The active enzyme in each step is shaded blue.

    6. FIGURE 21-2 (part 1) Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme system described later in the text. 1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. The mechanism of the first step of this reaction is given to illustrate the role of decarboxylation in facilitating condensation. The ß-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of ß oxidation, but in the reverse sequence: 2 the ß-keto group is reduced to an alcohol, 3 elimination of H2O creates a double bond, and 4 the double bond is reduced to form the corresponding saturated fatty acyl group.FIGURE 21-2 (part 1) Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme system described later in the text. 1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. The mechanism of the first step of this reaction is given to illustrate the role of decarboxylation in facilitating condensation. The ß-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of ß oxidation, but in the reverse sequence: 2 the ß-keto group is reduced to an alcohol, 3 elimination of H2O creates a double bond, and 4 the double bond is reduced to form the corresponding saturated fatty acyl group.

    7. FIGURE 21-2 (part 2) Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme system described later in the text. 1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. The mechanism of the first step of this reaction is given to illustrate the role of decarboxylation in facilitating condensation. The ß-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of ß oxidation, but in the reverse sequence: 2 the ß-keto group is reduced to an alcohol, 3 elimination of H2O creates a double bond, and 4 the double bond is reduced to form the corresponding saturated fatty acyl group.FIGURE 21-2 (part 2) Addition of two carbons to a growing fatty acyl chain: a four-step sequence. Each malonyl group and acetyl (or longer acyl) group is activated by a thioester that links it to fatty acid synthase, a multienzyme system described later in the text. 1 Condensation of an activated acyl group (an acetyl group from acetyl-CoA is the first acyl group) and two carbons derived from malonyl-CoA, with elimination of CO2 from the malonyl group, extends the acyl chain by two carbons. The mechanism of the first step of this reaction is given to illustrate the role of decarboxylation in facilitating condensation. The ß-keto product of this condensation is then reduced in three more steps nearly identical to the reactions of ß oxidation, but in the reverse sequence: 2 the ß-keto group is reduced to an alcohol, 3 elimination of H2O creates a double bond, and 4 the double bond is reduced to form the corresponding saturated fatty acyl group.

    8. FIGURE 21-3a The structure of fatty acid synthase type I systems. The low-resolution structures of (a) the mammalian (porcine; derived from PDB ID 2CF2) and (b) fungal enzyme systems (derived from PDB IDs 2UV9, 2UVA, 2UVB, and 2UVC) are shown. (a) All of the active sites in the mammalian system are located in different domains within a single large polypeptide chain. The different enzymatic activites are: ß-ketoacyl-ACP synthase (KS), malonyl/acetyl-CoA—ACP transferase (MAT), ß-hydroxyacyl-ACP dehydratase (DH), enoyl-ACP reductase (ER), and ß-ketoacyl-ACP reductase (KR). ACP is the acyl carrier protein. The linear arrangement of the domains in the polypeptide is shown in the lower panel. The seventh domain (TE) is a thioesterase that releases the palmitate product from ACP when the synthesis is completed. The ACP and TE domains are disordered in the crystal and are therefore not shown in the structure.FIGURE 21-3a The structure of fatty acid synthase type I systems. The low-resolution structures of (a) the mammalian (porcine; derived from PDB ID 2CF2) and (b) fungal enzyme systems (derived from PDB IDs 2UV9, 2UVA, 2UVB, and 2UVC) are shown. (a) All of the active sites in the mammalian system are located in different domains within a single large polypeptide chain. The different enzymatic activites are: ß-ketoacyl-ACP synthase (KS), malonyl/acetyl-CoA—ACP transferase (MAT), ß-hydroxyacyl-ACP dehydratase (DH), enoyl-ACP reductase (ER), and ß-ketoacyl-ACP reductase (KR). ACP is the acyl carrier protein. The linear arrangement of the domains in the polypeptide is shown in the lower panel. The seventh domain (TE) is a thioesterase that releases the palmitate product from ACP when the synthesis is completed. The ACP and TE domains are disordered in the crystal and are therefore not shown in the structure.

    9. FIGURE 21-4 (part 1) The overall process of palmitate synthesis. The fatty acyl chain grows by two-carbon units donated by activated malonate, with loss of CO2 at each step. The initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. After each two-carbon addition, reductions convert the growing chain to a saturated fatty acid of four, then six, then eight carbons, and so on. The final product is palmitate (16:0).FIGURE 21-4 (part 1) The overall process of palmitate synthesis. The fatty acyl chain grows by two-carbon units donated by activated malonate, with loss of CO2 at each step. The initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. After each two-carbon addition, reductions convert the growing chain to a saturated fatty acid of four, then six, then eight carbons, and so on. The final product is palmitate (16:0).

    10. FIGURE 21-4 (part 2) The overall process of palmitate synthesis. The fatty acyl chain grows by two-carbon units donated by activated malonate, with loss of CO2 at each step. The initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. After each two-carbon addition, reductions convert the growing chain to a saturated fatty acid of four, then six, then eight carbons, and so on. The final product is palmitate (16:0).FIGURE 21-4 (part 2) The overall process of palmitate synthesis. The fatty acyl chain grows by two-carbon units donated by activated malonate, with loss of CO2 at each step. The initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. After each two-carbon addition, reductions convert the growing chain to a saturated fatty acid of four, then six, then eight carbons, and so on. The final product is palmitate (16:0).

    11. FIGURE 21-5 Acyl carrier protein (ACP). The prosthetic group is 4'-phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A molecule. Its —SH group is the site of entry of malonyl groups during fatty acid synthesis.FIGURE 21-5 Acyl carrier protein (ACP). The prosthetic group is 4'-phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A molecule. Its —SH group is the site of entry of malonyl groups during fatty acid synthesis.

    12. FIGURE 21-6 Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    13. FIGURE 21-6 (part 1) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 1) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    14. FIGURE 21-6 (part 2) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 2) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    15. FIGURE 21-6 (part 3) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 3) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    16. FIGURE 21-6 (part 4) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 4) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    17. FIGURE 21-6 (part 5) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 5) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    18. FIGURE 21-6 (part 6) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 6) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    19. FIGURE 21-6 (part 7) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 7) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

    20. FIGURE 21-6 (part 8) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.FIGURE 21-6 (part 8) Sequence of events during synthesis of a fatty acid. The mammalian FAS I complex is shown schematically, with catalytic domains colored as in Figure 21-3. Each domain of the larger polypeptide represents one of the six enzymatic activities of the complex, arranged in a large, tight "S" shape. The acyl carrier protein (ACP) is not resolved in the crystal structure shown in Figure 21-3, but is attached to the KS domain. The phosphopantetheine arm of ACP ends in an —SH. After the first panel, the enzyme shown in color is the one that will act in the next step. As in Figure 21-4, the initial acetyl group is shaded yellow, C-1 and C-2 of malonate are shaded pink, and the carbon released as CO2 is shaded green. Steps 1 to 4 are described in the text.

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