Lecture 2- Fatty acid activation and carnitine shuttle.pptx

Activation of fatty acid

1. Subject Name: Intermediary Metabolism Subject Code : MTI 502 Unit No:1 Unit Name: Lipid Metabolism Dr. Arpita Gupte

2. Role of carnitine β –Oxidation of fatty acids

3. Digestion of fat

4. Utilization Stage 1 : Mobilization Hormone Sensitive Lipase Epinephrine , glucagon, ACTH triggers lipolysis Insulin inhibits lipolysis

5. The glycerol released - converted to glyceraldehyde-3-PO 4 - glycolysis - gluconeogenesis Fate of glycerol

6. Utilization stages Fatty acid must be activated : bound to coenzyme A Fatty acid must be transported into mitochondrial matrix: uses a shuttle mechanism Fatty acid repeatedly oxidized , cycling through 4 reactions: produces Acetyl CoA, FADH 2 , & NADH

7. Utilization Stage 2 : Activation Acyl-CoA Synthases ( Thiokinase ) of ER & outer mitochondrial membranes catalyze activation of long chain fatty acids, esterifying them to coenzyme A. This process is ATP-dependent , & occurs in 2 steps. There are different Acyl-CoA Synthases for fatty acids of different chain lengths. 

8. fatty acid + ATP + CoA-SH  acyl-CoA + AMP + 2 P i Summary of fatty acid activation: fatty acid + ATP  acyl-adenylate + PP i PP i    2 P i acyladenylate + HS-CoA  acyl-CoA + AMP Overall: Acyl CoA synthase Inorganic pyrophosphatase

9. The longer chain fatty acids cannot diffuse across mitochondrial membrane So must be transported Uses a carrier protein: carnitine (derivative of amino acid lysine ) : β - hydroxy , γ - trimethyl ammonium butyrate -Found in red meats & dairy products, can also be synthesized by the body. Utilization Stage 3 : Transport into mitochondria – Role of carnitine

10. Utilization Stage 3 : Transport into mitochondria Transfer of the fatty acid across the inner mitochondrial membrane involves carnitine .  Carnitine Palmitoyl Transferases catalyze transfer of a fatty acid between the thiol of Coenzyme A and the hydroxyl on carnitine

11. Utilization Stage 3 : Transport into mitochondria Carnitine-mediated transfer of the fatty acyl into the mitochondrial matrix is a 3-step process: 1. Carnitine Palmitoyl Transferase I , an enzyme on the cytosolic surface of the outer mitochondrial membrane, transfers a fatty acid from CoA to the OH on carnitine. 2. An antiporter in the inner mitochondrial membrane mediates exchange of carnitine for acylcarnitine . 3. Carnitine Palmitoyl Transferase II , an enzyme within the matrix, transfers the fatty acid from carnitine to CoA. (Carnitine exits the matrix in step 2.) The fatty acid is now esterified to CoA in the matrix.

12. Thank You