Question

Prior to a fatty acid (FA) being used as the input for beta-oxidation, it is activated and transitions from cytosol to mitochondria.

How is the FA activated and how is the activated FA is sent to the mitochondria matrix. Also explain how the breaking down of the FA in B-oxidation ends up producing big amounts of ATP (need to describe multiple metabolic reactions here)

Answer 1

Fatty acids (FA) are activated before they enter the mitochondrial matrix. Prior to activation, FA must be linked to CoA to form fatty acyl CoA. This reaction takes place in the outer membrane of the mitochondrial matrix. Adenosine triphosphate (ATP) drives the formation of fatty acyl CoA. Fatty acyl CoA is formed by the thioester linkage between the carboxyl group (COOH) of a fatty acid and the sulfhydryl group (-S-H) of CoA, yield AMP and pyrophosphate (PPi). The reaction is catalyzed by the enzyme acyl CoA synthetase (fatty acid thiokinase).

R-COOH + CoA-S-H + ATP <--> R-CO-S-CoA + AMP + PPi

This reaction is accomplished by (i) the reaction of fatty acid with ATP to form an acyl adenylate. In this reaction the COOH group of a fatty acid is bonded to the phosphoryl group of AMP and one PPi molecule is released.

R-COOH + ATP <--> R-CO-AMP + PPi

and (ii)  the reaction of sulfhydryl group of CoA with acyl adenylate to form acyl CoA and AMP.

R-CO-AMP + HS-CoA <--> R-CO-S-CoA + AMP

The activation of a fatty acid is accomplished by the .subsequent hydrolysis of the pyrophosphate (PPi) yield two inorganic phosphate molecules (Pi).

PPi + H2O --> 2 Pi

Fatty acids are activated on the outer mitochondrial membrane. Activated long-chain fatty acids are transported across the mitochondrial membrane need a special transport mechanism. This is achieved by conjugating cytoplasmic fatty acyl CoA to a zwitterionic alcohol called carnitine with the help of the enzyme carnitine acyl transferase (CAT I) and form fatty acyl carnitine. This fatty acyl carnitine is then trransported to the inner surface of the inner mitochondrial membrane and the enzyme carnitine acyl transferase II (CAT II) breaks fatty acyl carnitine to acyl CoA and carnitine and activated in the mitochondrion.

R-CO-S-CoA + carnitine <--> Acyl carnitine + HS-CoA

The breaking down of the FA in beta-oxidation ends up producing big amounts of ATP. Eight cycles of beta-oxidation required to complete the oxidation of a eighteen carbon fatty acid. This yield 9 acetyl-CoAs, 8 NADH molecules and 8 FADH2 molecules. 9 acetyl-CoAs enter into the citric acid cycle (CAC) to produce 9 GTP, 9 FADH2 molecules and 27 NADH molecules. So the total amount of ATP produced from beta-oxidation and citric acid cycle is

NADH - (8 beta oxidaion and 27 CAC) = 2.5 molecules of ATP/35 NADH = 87.5 ATP

FADH2  - (8 beta oxidaion and 27 CAC) = 1.5 molecules of ATP/17 FADH2 = 25.5 ATP

9 GTP = 9 ATP

Total ATP yield = 87.5 + 25.5 + 9 = 122 ATP. Two ATP molecules are required to activate FA activation. So 122 - 2 = 120 ATP molecules.