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BETA OXIDATION

OXIDATION OF FATTY ACIDS. BETA OXIDATION. OXIDATION OF FAT. The initial event in the utilization of fat as an energy source is the hydrolysis of triacylglycerol by lipases. Metabolism of Triacylglycerols in Tissues

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BETA OXIDATION

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  1. OXIDATION OF FATTY ACIDS BETA OXIDATION

  2. OXIDATION OF FAT • The initial event in the utilization of fat as an energy source is the hydrolysis of triacylglycerol by lipases

  3. Metabolism of Triacylglycerols in Tissues Epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone stimulate the adenylatecyclase of adipose cells, and thus cause lipolysis.

  4. Fatty • Mobilization of Stored Fat • Hormone-sensitive lipase initiates the hydrolysis of TGs to yield FAs (from either C-1 or C-3) and glycerol. Additional lipases then take over. • The FAs can either be exported to other tissues or can be metabolized to CO2.

  5. high malonyl CoA inhibits high palmitoyl CoA inhibits citrate stimulates TCA Cycle

  6. Step 1: Activation of fatty acids to acyl-CoA: Acyl-CoA synthetases are found in the endoplasmic reticulum, peroxisomes, and inside and on the outer membrane of mitochondria. Several acyl-CoA synthetases have been described, each for fatty acids of different chain length. Acyl CoA + AMP + 2Pi + 2H+ R-COO- + CoA + ATP + H20

  7. Transport of Acyl-CoAs into Mitochondria: • < 12 carbon fatty acyl CoAs passively diffuse through the • mitochondrial inner membrane; > 12 carbon fatty acyl CoAs are specifically transported across the inner membrane. Basic Strategy:Convert acyl CoA to an acyl carnitine derivative, which is then transported. Then regenerate the acyl CoA within the mitochondrial matrix. Reproduced from Stryer, Biochemistry, 4th Edition, p. 608.

  8. Carnitine acyltransferase Iis located on the outer mitochondrial membrane Carnitine acyltransferase II is located on the inner surface of the inner mitochondrial membrane.

  9. Regulation: The principal point of regulation of FA oxidation is via inhibition of carnitineacyltransferase I by malonylCoA.

  10. ß-oxidation of fatty acids involves successive cleavage with release of acetyl-CoA. Fatty acid oxidase are found in the mitochondrial matrix or inner membrane adjacent to the respiratory chain in the inner membrane.

  11. Catabolism of Fatty Acyl CoAs in the Mitochondrial Matrix • Degradation of FAs proceeds 2 carbons at a time, starting • from the carboxyl end. • - The reactions occur in the mitochondrial matrix. • Oxidation reactions directly feed reducing equivalents to • the respiratory chain to make ATP. • The released acetyl CoA enters the citric acid cycle which • will yield additional ATP.

  12. The Cyclic Reaction Sequence GeneratesFADH2 & NADH Several enzymes, known collectively as “fatty acid oxidase,”are found in the mitochondrial matrix or inner membrane adjacent to the respiratory chain. These catalyze the oxidation of acyl-CoA to acetyl-CoA, the system being coupled with the phosphorylation of ADP to ATP (Figure 22–3). Finally, forming acetyl-CoA and a new acyl- CoA two carbons shorter than the original acyl-CoA molecule. The acyl-CoA formed in the cleavage reaction reenters the oxidative pathway at reaction 2 (Figure 22–3). In this way, a long-chain fatty acid may be degraded completely to acetyl-CoA (C2 units). Since acetyl-CoA can be oxidized to CO2 and water via the citric acid cycle (which is also found within the mitochondria), the complete oxidation of fatty acids is achieved.

  13. β-Oxidation of FA 3 2 1 Oxidation βα Hydration βα Oxidation βα Thiolysis Split off the carboxy terminal 2-carbon fragment as acetyl CoA. Fatty Acyl CoA shortened by 2 carbon atoms The action will be at the β carbon. Per Cycle: 1 NADH, 1 FADH2, and 1 Acetyl CoA are generated. Modified from Nelson & Cox, Lehninger Principles of Biochemistry, 4th Edition, Fig. 17.8.

  14. Oxidation of fatty acids produces a large quantity of ATP: Palmitoyl CoA + 7 FAD + 7 NAD+ + 7 CoA + 7H2O 8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+ Oxidation of NADH - 3ATP '' FADH2 - 2 ATP '' Acetyl-CoA - 12 ATP7 FADH2 yields 147 NADH yields 218 acetyl-CoA yields 96Total 131 ATP2 high energy phosphate bonds are consumed in the activation of palmitateNet yield is 129 ATP or 129 X 51.6 = 6656 kJ

  15. Energy Yield of FA Oxidation One Cycle NADH 2.5 ATP FADH2 1.5 ATP Acetyl CoA 10 ATP (generated via citric acid cycle; i.e., 3 NADH + 1 FADH2 +1 substrate level phosphorylation) TOTAL = 14 ATP generated per cycle Example: Palmitate (16 carbons) 7 cycles of oxidation 28 ATP 8 acetyl CoAs produced 80 ATP Fatty acid activation - 2 ATP TOTAL = 106 ATP Initial activation step involves breaking both phosphoanhydride bonds in ATP; This is energetically equivalent to 2 ATP.

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