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  1. 1. Fatty Acid OxidationDR MUHAMMAD MUSTANSAR
  2. 2. FATTY ACID OXIDATION 1) Steps prior to FA oxidation (β-oxidation). 2) Steps involved in FA oxidation (β-oxidation). 3) Metabolism of ketone bodies.2
  3. 3. Importance The process of FA oxidation is termed β- oxidation since it occurs through the sequential removal of 2-carbon units by oxidation at the β-carbon position of the fatty acyl-CoA molecule. Although FAs are both oxidized to acetyl-CoA and synthesized from acetyl-CoA, FA oxidation is not the simple reverse of FA biosynthesis but an entirely different process taking place in a separate compartment of the cell.3
  4. 4. The oxidation of FAs yields significantly more energy per carbon atom than does the oxidation of carbohydrates. The net result of the oxidation of one mole of oleic acid (18-carbon FA) will be 146 moles of ATP (2 mole equivalents are used during the activation of the FA), as compared to 114 moles from an equivalent number of glucose carbon atoms.4
  5. 5. Increased FA oxidation is a characteristic of starvation and of diabetes mellitus, leading to ketone body production by the liver. Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal.5
  6. 6. 6
  7. 7. Steps prior to fatty acid oxidation (β-oxidation).7
  8. 8. FAs Are Transported in the Blood.  In the circulatory system, longer-chain FA are combined with albumin, and in the cell they are attached to a fatty acid-binding protein (FAbP).  FA enter cells by diffusion through the lipid plasma membrane and binds to FAbP intracellularly and facilitate its transport to the mitochondrion.  Shorter-chain fatty acids are more water-soluble and exist as the unionized acid or as a fatty acid8 anion.
  9. 9. FAs Are Activated before Being catabolized. FAs must first be converted to an active intermediate before they can be catabolized. This is the only step in the complete degradation of a FA that requires energy from ATP.9
  10. 10. In the presence of ATP and coenzyme A, the enzyme acyl-CoA synthetase catalyzes the conversion of a FA to an "active FA" or acyl-CoA, which uses one high-energy phosphate with the formation of AMP and PPi. This occurs at the outer mitochondrial membrane.10
  11. 11. Transport of long-chain FA into the mitochondria.The transport of fatty acyl-CoA into the mitochondria is accomplished via an acyl- carnitine intermediate, which itself is generated by the action of carnitine palmitoyltransferase I (CPT I, also called carnitine acyltransferase I, CA I) an enzyme that resides in the outer mitochondrial membrane.11
  12. 12. The acyl-carnitine molecule then is transported into the mitochondria where carnitine palmitoyltransferase II (CPT II, also called carnitine acyltransferase II, CA II) catalyzes the regeneration of the fatty acyl-CoA molecule.12
  13. 13. Figure: Transportation of FAs.  Role of carnitine in the transport of long-chain FAs through the inner mitochondrial membrane.  Long-chain acyl-CoA cannot pass through the inner mitochondrial membrane, but its metabolic product which is acylcarnitine, can.13
  14. 14. 14
  15. 15. Steps involved in FA oxidation (β-oxidation).15
  16. 16. FAs with an odd number of carbon atoms are oxidized by the pathway of β- oxidation, producing acetyl-CoA, until a three-carbon (propionyl-CoA) residue remains. This compound is converted to succinyl- CoA, a constituent of the TCA cycle.16
  17. 17. Figure: Conversion of Propionyl-CoA to Succinyl-CoA.17
  18. 18. β-Oxidation of FAs Involves Successive Cleavage with Release of Acetyl-CoA. In β-oxidation, two carbons at a time are cleaved from acyl-CoA molecules, starting at the carboxyl end.18
  19. 19. The chain is broken between the α(2)- and β(3)-carbon atoms—hence the name β-oxidation. The two-carbon units formed are acetyl-CoA; thus, palmitoyl-CoA forms eight acetyl-CoA molecules.19
  20. 20. 20 Figure: Overview of β-oxidation of FAs.
  21. 21. Figure: Summary of FA oxidation.21
  22. 22. Figure: Cont’.22
  23. 23. Figure: Cont’.23
  24. 24. Figure: β-oxidation.24
  25. 25. 25 Figure: β-oxidation.
  26. 26. 26 Figure: Cont.’
  27. 27. Approximately half of the FAs in the human diet are unsaturated, consisting of cis double bonds, with oleate and linoleate being the most common. The oxidation of unsaturated FA is essentially the same process as for saturated fats, except when a double bond is encountered. In such a case, the bond is isomerized by a specific enoyl-CoA isomerase and oxidation continues.27
  28. 28. In the case of linoleate, the presence of the Δ 12 unsaturation results in the formation of a dienoyl- CoA during oxidation.This molecule is the substrate for an additional oxidizing enzyme, the NADPH requiring 2,4- dienoyl-CoA reductase.β-oxidation of saturated FA creates the trans double bond between the α- and β- carbons. So in unsaturated FA, the cis double bonds must be isomerized to trans double bonds. 28
  29. 29. Figure: Sequence of reactions in the oxidation of unsaturated FAs, e.g. linoleic acid.29
  30. 30. Figure: Cont.’30
  31. 31. At the end of this class, students should be able to know that / the:- 1) Steps prior to fatty acid oxidation (β-oxidation). 2) Steps involved in fatty acid oxidation (β-oxidation). 3)Metabolism of ketone bodies.31
  32. 32. During high rates of FA oxidation, primarily in the liver, large amounts of acetyl-CoA are generated.These exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies, or ketogenesis.The ketone bodies are acetoacetate, β- hydroxybutyrate, and acetone and they serve as major fuels for tissues. 32
  33. 33. Ketogenesis allows the heart and skeletal muscles mainly to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain. However, the brain, intestine, adipocytes, and the fetus can use ketone bodies as fuel during prolonged fasting with the only exception of liver and RBC that are not able to utilize ketone bodies.33
  34. 34. Figure: Interrelationships of the ketone bodies. D(–)-3-hydroxybutyrate dehydrogenase is a mitochondrial enzyme.34
  35. 35. Figure: Ketogenesis.35
  36. 36. Figure: Utilization of the Ketone Bodies.36
  37. 37. The first enzyme is present in all tissues except the liver. Importantly its absence allows the liver to not utilize ketone bodies. This ensures that extrahepatic tissues have access to ketone bodies as a fuel source during prolonged fasting and starvation.37
  38. 38. Figure: Transport of ketone bodies from the liver and pathways ofutilization and oxidation in extrahepatic tissues.38
  39. 39.  In extrahepatic tissues, acetoacetate is activated to acetoacetyl- CoA by succinyl-CoA-acetoacetate CoA transferase.  CoA is transferred from succinyl-CoA to form acetoacetyl- CoA.  With the addition of a CoA, the acetoacetyl-CoA is split into two acetyl-CoAs by thiolase and oxidized in the TCA cycle.39
  40. 40.  In vivo, the liver appears to be the only organ in nonruminants to add significant quantities of ketone bodies to the blood.  Extrahepatic tissues utilize them as respiratory substrates (acetone).  The net flow of ketone bodies from the liver to the extrahepatic tissues results from active hepatic synthesis coupled with no utilization of ketone bodies by liver.  The reverse situation occurs in extrahepatic tissues.40
  41. 41. Figure: Formation, utilization, and excretion of ketone41 bodies. (The main pathway is indicated by the solid arrows.)
  42. 42. In most cases, ketonemia is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues. While acetoacetate and hydroxybutyrate are readily oxidized by extrahepatic tissues, acetone is difficult to oxidize in vivo and to a large extent is volatilized in the lungs.42
  43. 43. Clinical Significance  Diabetic ketoacidosis (DKA) is the situation of increased production of acetyl-CoA that leads to ketone body production that exceeds the ability of peripheral tissues to oxidize them.  Ketone bodies are relatively strong acids (pK a around 3.5), and their increase lowers the pH of the blood.  This acidification of the blood is dangerous chiefly because it impairs the ability of hemoglobin to bind oxygen.43
  44. 44. Ketoacidosis can be smelled on a persons breath. This is due to acetone, a direct byproduct of the spontaneous decomposition of acetoacetate. It is often described as smelling like fruit or nail polish remover.44