Beta oxidation
Beta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in the mitochondria to generate Acetyl-CoA, the entry molecule for the Krebs Cycle. Once inside the mitochondria, the β-oxidation of fatty acids occurs via four recurring steps:
Oxidation by FAD
The first step is the oxidation of the fatty acid by FAD. The following reaction is catalyzed by acyl CoA dehydrogenase:
The enzyme catalyzes the formation of a double bond between the C-2 and C-3. The end product is trans-Δ2-enoyl-CoA.
Hydration
The next step is the hydration of the bond between C-2 and C-3. This reaction is catalyzed by enoyl CoA hydratase. The reaction is stereospecific, forming only the L isomer.
The end product is L-3-hydroxyacyl CoA.
Oxidation by NAD+
The third step is the oxidation of L-3-hydroxyacyl CoA by NAD+, catalyzed by L-3-hydroxyacyl CoA dehydrogenase. This converts the hydroxyl group into a keto group.
The end product is 3-ketoacyl CoA.
Thiolysis
The final step is the cleavage of 3-ketoacyl CoA by the thiol group of another molecule of CoA. This reaction is catalyzed by Β-ketothiolase. The thiol is inserted between C-2 and C-3, which yields an acetyl CoA molecule and an acyl CoA molecule, which is two carbons shorter.
This process continues until the entire chain is cleaved into acetyl CoA units. For every cycle, one molecule of FADH2, NADH and acetyl CoA are formed.
β-oxidation of unsaturated fatty acids
β-oxidation of unsaturated fatty acids poses a problem since the location of a cis bond can prevent the formation of a trans-δ2 bond. These situations are handled by an additional two enzymes: cis-δ3-Enoyl CoA isomerase and 2,4 Dienoyl CoA reductase. Whatever the conformation of the hydrocarbon chain, β-oxidation occurs normally until the acyl CoA (because of the presence of a double bond) is not an appropriate substrate for acyl CoA dehydrogenase, or enoyl CoA hydratase.
If the acyl CoA contains a cis-Δ3 bond, then the isomerase will convert the bond to a trans-Δ2 bond, which is a regular substrate.
If the acyl CoA contains a cis-Δ4 double bond, then its dehydrogenation yields a 2,4-dienoyl intermediate, which is not a substrate for enoyl CoA hydratase. However, the enzyme 2,4-Dienoyl CoA reductase reduces the intermediate, using NADPH, into trans-Δ3-enoyl CoA. As in the above case, this compound is converted into a suitable intermediate by cis-Δ3-Enoyl CoA isomerase.
To summarize, odd numbered double bonds are handled by the isomerase, and even numbered bonds by the reductase (which creates an odd numbered double bond) and the isomerase.
β-oxidation of odd-numbered chains
Chains with an odd-number of carbons are oxidized in the same manner as even-numbered chains, but the final products are propionyl CoA and acetyl CoA. Propionyl CoA is converted into succinyl CoA (which is an intermediate in the citric acid cycle) in a reaction that involves Vitamin B12. Succinyl CoA can then enter the citric acid cycle. Because it cannot be completely metabolized in the citric acid cycle, the products of its partial reaction must be removed in a process called cataplerosis. This allows regeneration of the citric acid cycle intermediates, possibly an important process in certain metabolic diseases.
Energy yield
The ATP yield for every oxidation cycle is 14 ATP, broken down as follows:
- 1 FADH2 x 1.5 ATP = 1.5 ATP
- 1 NADH x 2.5 ATP = 2.5 ATP
- 1 acetyl CoA x 10 ATP = 10 ATP
For an even-numbered saturated fat (C2n), n - 1 oxidations are necessary and the final process yields an additional acetyl CoA. In addition, two equivalents of ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as: (n - 1) * 14 + 10 - 2.
For instance, the ATP yield of palmitate (C16, n = 8) is:
- (8 - 1) * 14 + 10 - 2
- 106 ATP
or
- 7 FADH2 x 1.5 ATP = 10.5 ATP
- 7 NADH x 2.5 ATP = 17.5 ATP
- 8 acetyl CoA x 10 ATP = 80 ATP
- ATP equivalent used during activation = -2
- Total: 106 ATP
Oxidation in peroxisomes
Fatty acid oxidation also occurs in peroxisomes. However, the oxidation ceases at octanyl CoA. One significant difference is that oxidation in peroxisomes is not coupled to ATP synthesis. Instead, the high-potential electrons are transferred to O2, which yields H2O2. The enzyme catalase, found exclusively in peroxisomes, converts the hydrogen peroxide into water and oxygen.
See also