Lipid catabolism (fatty acid oxidation)
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1) Fatty acids undergo beta-oxidation in the mitochondria to break them down into acetyl-CoA units, releasing energy. 2) Beta-oxidation involves a four-step cycle that removes two-carbon acetyl-CoA units from the fatty acid. 3) The complete breakdown of a fatty acid like stearic acid yields 9 acetyl-CoA molecules which enter the citric acid cycle, producing a total of 146 ATP molecules through electron transport chain reactions.
Lipid catabolism (fatty acid oxidation)
- 1. LECTURE NOTES: PHARM. BIOCHEMISTRY DR. USMAN SALEEM 1 Fatty Acid Oxidation Over View As early as 1904, Franz Knoop, proposed that the body utilizes fatty acids as an energy source by breaking them down into fragments. Prior to fragmentation, the -carbon (the second carbon atom from the COOH group) is oxidized: The name -oxidation has its origin in Knoop’s prediction. Definition The biochemical pathway that degrades fatty acids to acetyl CoA by removing two carbons at a time and yielding energy. Location The -oxidation of fatty acids occur in several tissues, including liver, muscle, and adipose tissue. The erythrocytes and brain cannot use fatty acids and so continue to rely on glucose during normal periods of fasting. Erythrocytes lack mitochondria, and fatty acids do not cross the blood-brain barrier efficiently. Short and medium-chain fatty acids diffuse freely into mitochondria while long chain fatty acids are transported into mitochondrion by a carnitine shuttle to be oxidized. Steps of -Oxidation for Fatty Acids. A. Activation of Fatty Acid Long chain fatty acids that enter tissue cells cannot be oxidized to produce energy until they pass through the mitochondrial membrane. This cannot occur until the fatty acid is converted into fatty acyl CoA by reaction with coenzyme A (CoA-SH).
- 2. LECTURE NOTES: PHARM. BIOCHEMISTRY DR. USMAN SALEEM 2 This reaction is catalyzed by acyl CoA synthetase and is referred to as activation of the fatty acid because the fatty acyl CoA is a high-energy compound. The energy needed for its synthesis is provided by the hydrolysis of ATP to AMP and PPi. The activated fatty acid must be transported into the mitochondrion so that the rest of the oxidation process can proceed. B. Transport of Fatty Acyl-CoA into Mitochondria The acyl-CoA can cross the outer mitochondrial membrane but not the inner membrane. In the intermembrane space, the acyl group is transferred to carnitine by transesterification to form acyl-carnitine; this reaction is catalyzed by the enzyme carnitine acyltransferase-I, which is located on the outer face of the inner membrane. The acyl-carnitine passes through the inner membrane via a specific carnitine/acyl-carnitine transporter called carnitine translocase. Once in the matrix, the acyl group is transferred from carnitine to mitochondrial CoA-SH by another enzyme called carnitine acyltransferase-II located on the inner face of the membrane. C. -Oxidation Once the fatty acid in the form of acyl CoA is inside the mitochondrion, it is degraded in a catabolic process called -oxidation. The -oxidation of saturated fatty acids involves a cycle of four enzyme-catalyzed reactions. 1) Oxidation by FAD 2) Hydration 3) Oxidation by NAD 4) Cleavage 1) Oxidation by FAD: The acyl-CoA is oxidized to an , unsaturated acyl-CoA (also called a -enoyl- CoA). This reaction is catalyzed by an FAD-dependent acyl-CoA dehydrogenase. The product has the trans arrangement at the double bond. 2) Hydration: The unsaturated acyl-CoA is hydrated to produce a -hydroxyacyl-CoA. This reaction is catalyzed by the enzyme enoyl-CoA hydratase. 3) Oxidation by FAD: A second oxidation reaction is catalyzed by β-hydroxyacyl-CoA dehydrogenase, an NAD+ -dependent enzyme. The product is a β-ketoacyl-CoA.
- 3. LECTURE NOTES: PHARM. BIOCHEMISTRY DR. USMAN SALEEM 3 4) Cleavage: The enzyme thiolase catalyze the cleavage of the terminal C2 fragment (an acetyl CoA) from the chain and the rest of the molecule is bonded to a new molecule of coenzyme A (acyl CoA). The new fatty acyl-CoA that is two carbons shorter than the original molecule enters the-oxidation process and sequence is repeated until the fatty acyl-CoA is completely degraded to acetyl CoA. Fig: The -Oxidation of Saturated Fatty Acids Stearic Acid: R = –CH2 – (CH2)12 – CH3
- 4. LECTURE NOTES: PHARM. BIOCHEMISTRY DR. USMAN SALEEM 4 When a fatty acid with an even number of carbon atoms undergoes successive rounds of the -oxidation cycle, the product is acetyl-CoA. The number of molecules of acetyl-CoA produced is equal to half the number of carbon atoms in the original fatty acid. For example, stearic acid contains 18 carbon atoms and gives rise to 9 molecules of acetyl-CoA. The Energy Yield from the Oxidation of Fatty Acids To calculate the energy yield from fatty acid, we shall use the oxidation of stearic acid, the C18 saturated fatty acid, as an example. As a stearyl CoA molecule (18 carbons) passes through the -oxidation spiral, 9 acetyl CoA, 8 FADH2, and 8 NADH molecules are produced. When the FADH2 and NADH molecules enter the electron transport chain, each FADH2 yields 2 ATP molecules, and each NADH yields 3 ATP molecules. The oxidation of each acetyl CoA by the citric acid cycle yield 12 ATP molecules. Two high energy phosphate bonds are consumed in the activation of stearic acid in which ATP is split into AMP and PPi. Thus, from the complete oxidation of a stearic acid, we obtain a total of 146 ATP molecules. The Balance Sheet for Oxidation of One Molecule of Stearic Acid Chemical Step Happens Number of ATP molecules produced Activation (stearic acid stearyl CoA) Dehydrogenation (acyl CoA trans-enoyl CoA), producing FADH2 Dehydrogenation (hydroxylacyl CoA ketoacyl CoA , producing NADH + H+ Oxidation of acetyl CoA by citric acid cycle, producing 12 ATP Once 8 times 8 times 9 times -2 16 24 108 Total: 146
- 5. LECTURE NOTES: PHARM. BIOCHEMISTRY DR. USMAN SALEEM 5 Summery Fatty acids are activated and transported to the mitochondrial matrix for further catabolism. The breakdown of fatty acids takes place in the mitochondrial matrix and proceeds by successive removal of two-carbon units as acetyl-CoA. Each cleavage of a two-carbon moiety requires a four-step reaction sequence called -oxidation. The b-oxidation of unsaturated fatty acids proceeds in the same way. An extra step is involved, in which the cis double bond is isomerized to a trans bond, but otherwise the spiral is the same.