Bài giảng môn Sinh học - Chapter 5: Lipid metabolism

CHAPTER 5. LIPID METABOLISMINTERNATIONAL UNIVERSITYSCHOOL OF BIOTECHNOLOGY BIOCHEMISTRY 1Learning objectivesDescribe the metabolism of fatty acids. The two main components of fatty acid metabolism are β oxidation and fatty acid synthesis. Understand that the fatty-acid breakdown reactions of β oxidation result in the formation of reduced cofactors and acetyl-CoA molecules, which can be further catabolized to release free energy.Understand that the oxidation of unsaturated, odd-chain, and very-long-chain fatty acids requires additional enzymes, some of them in peroxisomes.Understand how fatty acid synthesis resembles and differs from β oxidation.2Content1. Fatty acid activation2. Steps of β oxidation3. Energy yield of oxidation4. Oxidation of palmitate5. Unsaturated fatty acids6. Odd-chain fatty acids3Content7. Very long-chain fatty acids8. Synthesis vs. oxidation9. Steps of synthesis10. Palmitate synthesis11. Fatty acid synthasesConclusion4Fatty Acid Metabolism LEARNING OBJECTIVES Fatty acids are an important energy source, for they yield over twice as much energy as an equal mass of carbohydrate or protein. In humans, the primary dietary source of fatty acids is triacylglycerols. This lecture will describe the metabolism of fatty acids. The two main components of fatty acid metabolism are β oxidation and fatty acid synthesis. Upon completion of this lecture, you will understand that the fatty-acid breakdown reactions of β oxidation result in the formation of reduced cofactors and acetyl-CoA molecules, which can be further catabolized to release free energy. You will also understand that the oxidation of unsaturated, odd-chain, and very-long-chain fatty acids requires additional enzymes, some of them in peroxisomes. In addition, you will understand how fatty acid synthesis resembles and differs from β oxidation.567FATTY ACID ACTIVATION Triacylglycerols are carried by lipoproteins to tissues, where hydrolysis releases their fatty acids from the glycerol backbone. Fatty acids enter the cell and are activated in the cytosol. This activation costs two ATP equivalents per fatty acid. Most of the activated fatty acids are then shuttled into the mitochondria for β oxidation, but a small percentage are carried to the peroxisomes.89101112STEPS OF β OXIDATION The activated fatty acid is called a fatty acyl-coenzyme A, or fatty acyl-CoA. In the first step of β oxidation, an acyl-CoA dehydrogenase catalyzes the oxidation of the acyl group, resulting the formation of a double bond between carbons two and three. The two electrons removed from the acyl group are transferred to an FAD prosthetic group. These electrons are transferre to ubiquinone through a series of electron transfer reactions. In the second step of β oxidation, a hydratase adds a molecule of water across the double bond produced in the first step. In the third step of β oxidation, another dehydrogenase catalyzes the oxidation of the hydroxyacyl group. In this case, NAD+ is the cofactor. The fourth and final step of β oxidation is called thiolysis. In this step, a thiolase catalyzes the release of acetyl-CoA from the ketoacyl-CoA.1314151617ENERGY YIELD OF OXIDATION One round of β oxidation yields three products—one ubiquinol cofactor, one NADH cofactor, and one molecule of acetyl-CoA. During the citric acid cycle, the acetyl-CoA is used to produce three NADH cofactors, one ubiquinol cofactor, and one molecule of GTP. During oxidative phosphorylation, each ubiquinol cofactor is used to produce two ATP molecules, and each NADH cofactor is used to produce three ATP molecules. The GTP molecule is equivalent to one ATP molecule. In all, one round of β oxidation produces the equivalent of 17 molecules of ATP. Since two ATP equivalents were used for the activation step, the net yield is 15 molecules of ATP.181920212223OXIDATION OF PALMITATE The fatty acid we started with was palmitate. Let’s determine the energy yield for the complete β oxidation of this 16-carbon fatty acid. Palmitate goes through seven rounds of β oxidation, each of which yields products equivalent to seventeen molecules of ATP. The final product of complete β oxidation is an additional molecule of acetyl-CoA, which is equivalent to twelve molecules of ATP. In all, the complete β oxidation of palmitate produces 131 molecules of ATP. Subtracting the initial ATP investment for activation yields 129 molecules of ATP from a single molecule of palmitate.24252627UNSATURATED FATTY ACIDS Many common fatty acids contain cis double bonds. These double bonds present an obstacle to the enzymes of β oxidation. Let’s follow the oxidation of linoleate to see how these metabolic obstacles are removed. 28UNSATURATED FATTY ACIDS The first three rounds proceed normally. However, the enoyl-CoA that begins the fourth round has a double bond between the third and fourth carbon atoms and is not recognized by acyl-CoA dehydrogenase. Instead, an enoyl-CoA isomerase converts the cis 3-4 double bond to a trans 2-3 double bond so that β oxidation can continue. Since the enoyl-CoA isomerase reaction bypasses the ubiquinol-producing step of this round of β oxidation, the energy yield for this round is 15 ATP molecules, rather than 17. 29UNSATURATED FATTY ACIDS Another problem arises in the fifth round. Step one proceeds as normal, but the resulting molecule has two double bonds: one at the 2-3 position, and one at the 4-5 position. The enoyl-CoA hydratase of step two cannot recognize this dienoyl-CoA. This problem is overcome by reducing the dienoyl group, but the reaction requires an investment of one NADPH cofactor, which is equivalent to three ATP molecules. After enoyl-CoA isomerase acts, the acyl group can continue through the pathway.3031323334UNSATURATED FATTY ACIDS Linoleate goes through eight rounds of β oxidation. If linoleate did not have double bonds, this would result in a total of 146 molecules of ATP. However, because of the corrections for the double bonds, the total yield is 141 molecules of ATP per molecule of linoleate. In general, double bonds that begin at odd-numbered positions cost the equivalent of two ATP molecules, and double bonds beginning at even-numbered positions cost the equivalent of three ATP molecules.353637ODD-CHAIN FATTY ACIDS Most fatty acids have an even number of carbon atoms, since they are built from two-atom acetyl units, as we’ll see momentarily. However, some plant and bacterial fatty acids have an odd number of carbon atoms. Such odd-chain fatty acids yield a three-carbon propionyl-CoA after the final round of β oxidation. This intermediate is further metabolized through a series of reactions, both in the mitochondria and in the cytosol. Essentially, to get rid of the one extracarbon atom, one ATP molecule was invested, and the process produced the equivalent of nine additional ATP. Therefore, to calculate the energy yield of the complete β oxidation of an odd-chain fatty acid, add eight to the total for a fatty acid with one less carbon atom.38394041 VERY-LONG-CHAIN FATTY ACIDS Fatty acids with chains that contain twenty-two or more carbon atoms are called very-long-chain fatty acids. While shorter fatty acids are oxidized in the mitochondria, very-long-chain fatty acids begin β oxidation in the peroxisomes. This process is almost identical to β oxidation in the mitochondria, with one key difference. Instead of reducing ubiquinone in the first step, the peroxisomes produce hydrogen peroxide. This peroxide can be used in other reactions to oxidize toxic substances in the cell. 42 VERY-LONG-CHAIN FATTY ACIDS Each round of b oxidation in the peroxisomes produces the equivalent of fifteen molecules of ATP—two less than β oxidation in the mitochondria. However, peroxisomes usually do not completely degrade the fatty acids. Because the enzymes in peroxisomes have a low affinity for short-chain fatty acids, shortened fatty acids are transported to the mitochondria to finish b oxidation.4344454647SYNTHESIS VS. OXIDATION At first glance, fatty acid synthesis appears to be the exact reverse of β oxidation—fatty acyl groups are built and degraded two carbon atoms at a time, and several of the reaction intermediates in the two pathways are similar or identical. However, the pathway for fatty acid synthesis can not be the exact reverse of β oxidation; since β oxidation is thermodynamically favorable, the reverse process is thermodynamically unfavorable. Thus, fatty acid synthesis requires a large investment of energy in the form of ATP.4849STEPS OF SYNTHESIS Let’s take a closer look at the steps of fatty acid synthesis. Before fatty acid synthesis can begin, an acetyl group must be transferred from coenzyme-A to an acyl carrier protein, called ACP. The first step in the cycle adds a two-carbon unit to the growing fatty acid. The two carbon atoms come from malonyl-CoA, which is produced from acetyl-CoA in a reaction requiring one molecule of ATP. In the second step, NADPH is used to reduce the ketoacyl-ACP from step one. In the third step, hydroxyacyl-ACP dehydrase catalyzes the removal of a water molecule from the hydroxyacyl-ACP produced in step two. In the fourth step, a second NADPH-dependent reduction converts the enoyl-ACP produced in step three to a fatty acyl-ACP two carbon atoms longer than the starting substrate. In all, adding two carbon atoms to the fatty acid costs the cell one ATP and two NADPH molecules. 505152535455PALMITATE SYNTHESIS Palmitate synthesis requires seven rounds of fatty acid synthesis. In all, this costs the cell 49 ATP equivalents. After the final round of fatty acid synthesis, a fatty acyl thioesterase catalyzes the removal of the fatty acid from the acyl carrier protein.56575859FATTY ACID SYNTHASES In bacteria and chloroplasts, fatty acid synthesis is carried out by several enzymes. In mammals, the main reactions of fatty acid synthesis are carried out by one multifunctional enzyme made of two identical polypeptides. Packaging several enzyme activities into one multifunctional protein like mammalian fatty acid synthase allows the enzymes to be synthesized and controlled in a coordinated fashion. Also, the product of one reaction can quickly diffuse to the next active site.6061CONCLUSION Fatty acid metabolism is important to the function of many cells. Note that in fatty acid synthesis, the chain is extended two carbon atoms at a time, at the expense of ATP. In fatty acid oxidation, the chain is degraded two carbon atoms at a time, producing ATP. The two pathways are regulated so that a cell can synthesize energy-storing fatty acids in times of plenty, and oxidize the fatty acids when the cell needs to generate ATP.6263Thank you for your kindly listening64