BETA OXIDATION OF FATTY ACIDS: STEPS, REACTIONS, PRODUCTS, REGULATION - BIOLOGY - 2025

The beta oxidation of fatty acids is the route of the catabolism (degradation) of fatty acids, whose main function is the production or "release" of the energy contained in the bonds of these molecules.

This route was discovered in 1904 thanks to the experiments carried out by the German Franz Knoop, which consisted in the administration, to experimental rats, of fatty acids whose final methyl group had been modified with a phenyl group.

Diagram of the beta oxidation of fatty acids (Source: Arturo González Laguna via Wikimedia Commons)

Knoop expected the catabolism products of these "analog" fatty acids to follow pathways similar to the oxidation pathway of normal (unmodified natural) fatty acids. However, he found that there were differences in the products obtained as a function of the number of carbon atoms of the fatty acids.

With these results, Knoop proposed that the degradation occurred in "steps", beginning with an "attack" on the β carbon (the one at position 3 with respect to the terminal carboxyl group), releasing fragments of two carbon atoms.

It was later shown that the process requires energy in the form of ATP, which is produced in the mitochondria and that the fragments of two carbon atoms enter the Krebs cycle as acetyl-CoA.

In short, beta oxidation of fatty acids involves activation of the terminal carboxyl group, transport of the activated fatty acid into the mitochondrial matrix, and two-by-two carbon "stepped" oxidation from the carboxyl group.

Like many anabolic and catabolic processes, this route is regulated, since it merits the mobilization of “reserve” fatty acids when the other catabolic routes are not sufficient to meet the cellular and body energy demands.

Steps and reactions

Fatty acids are predominantly in the cytosol, whether they come from biosynthetic pathways or from fat deposits that are stored from ingested food (which must enter cells).

- Activation of fatty acids and transport to the mitochondria

The activation of fatty acids requires the use of an ATP molecule and has to do with the formation of acyl thioester conjugates with coenzyme A.

This activation is catalyzed by a group of enzymes called acetyl-CoA ligases specific to the chain length of each fatty acid. Some of these enzymes activate fatty acids as they are transported into the mitochondrial matrix, as they are embedded in the outer mitochondrial membrane.

Activation of fatty acids (Source: Jag123 at English Wikipedia via Wikimedia Commons)

The activation process occurs in two steps, first producing an acyl adenylate from the activated fatty acid with ATP, where a pyrophosphate molecule (PPi) is released. The carboxyl group activated by ATP is then attacked by the thiol group of coenzyme A to form acyl-CoA.

The translocation of acyl-CoA through the mitochondrial membrane is achieved by a transport system known as the carnitine shuttle.

- Beta oxidation of saturated fatty acids with an even number of carbon atoms

The degradation of fatty acids is a cyclical path, since the release of each fragment of two carbon atoms is immediately followed by another, until reaching the full length of the molecule. The reactions that have part in this process are the following:

- Dehydrogenation.

- Hydration of a double bond.

- Dehydrogenation of a hydroxyl group.

- Fragmentation by the attack of an acetyl-CoA molecule on the β carbon.

Reaction 1: first dehydrogenation

It consists of the formation of a double bond between the α-carbon and the β-carbon by eliminating two hydrogen atoms. It is catalyzed by an enzyme acyl-CoA dehydrogenase, which forms a molecule of trans∆2-enoyl-S-CoA and a molecule of FAD + (cofactor).

Reactions 2 and 3: hydration and dehydrogenation

Hydration is catalyzed by enoyl-CoA hydratase, while dehydrogenation is mediated by 3-hydroxyacyl-CoA dehydrogenase, and the latter reaction depends on the cofactor NAD +.

The hydration of trans∆2-enoyl-S-CoA gives rise to a 3-hydroxyacyl-CoA, whose dehydrogenation produces a 3-ketoacyl-CoA molecule and a NADH + H.

The FADH2 and NADH produced in the first three reactions of beta oxidation are reoxidized through the electron transport chain, thanks to which they participate in the production of ATP, 2 molecules for each FADH2 and 3 molecules for each NADH.

Reaction 4: fragmentation

Each cycle of beta oxidation that removes a molecule with two carbon atoms ends with the “thiolytic” cleavage of the keto carbon, which is attacked by coenzyme A at the bond between the α and β carbons.

This reaction is catalyzed by the enzyme β-ketothiolase or thiolase, and its products are one molecule of acyl-CoA (the activated fatty acid with two fewer carbon atoms) and one of acetyl-CoA.

- Beta oxidation of saturated fatty acids with an odd number of carbon atoms

In fatty acids with an odd number of carbon atoms (which are not very abundant), the molecule of the last degradation cycle has 5 carbon atoms, so its fragmentation produces an acetyl-CoA molecule (which enters the cycle of Krebs) and another of propionyl-CoA.

Propionyl-CoA must be carboxylated (reaction dependent on ATP and bicarbonate) by the enzyme propionyl-CoA carboxylase, thereby forming a compound known as D-methylmalonyl-CoA, which must be epimerized to its "L" form.

Beta oxidation of odd-numbered fatty acids (Source: Eleska via Wikimedia Commons)

The compound resulting from epimerization is then converted into succinyl-CoA by the action of the enzyme L-methylmalonyl-CoA mutase, and this molecule, as well as acetyl-CoA, enters the citric acid cycle.

- Beta oxidation of unsaturated fatty acids

Many cellular lipids have unsaturated fatty acid chains, that is, they have one or more double bonds between their carbon atoms.

The oxidation of these fatty acids is a little different from that of saturated fatty acids, since two additional enzymes, enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase, are in charge of eliminating these unsaturations so that these fatty acids may be a substrate for the enzyme enoyl-CoA hydratase.

Beta oxidation of unsaturated fatty acids (Source: Hajime7basketball via Wikimedia Commons)

Enoyl-CoA isomerase acts on monounsaturated fatty acids (with only one unsaturation), meanwhile the enzyme 2,4-dienoyl-CoA reductase reacts with polyunsaturated fatty acids (with two or more unsaturations).

- Beta extramitochondrial oxidation

The beta oxidation of fatty acids can also occur inside other cytosolic organelles such as peroxisomes, for example, with the difference that the electrons that are transferred to FAD + are not delivered to the respiratory chain, but directly to oxygen.

This reaction produces hydrogen peroxide (oxygen is reduced), a compound that is eliminated by the catalase enzyme, specific to these organelles.

Products of beta oxidation

Fatty acid oxidation produces much more energy than carbohydrate breakdown. The main product of beta oxidation is the acetyl-CoA produced in each step of the cyclic portion of the path, however, other products are:

- AMP, H + and pyrophosphate (PPi), produced during activation.

- FADH2 and NADH, for each acetyl-CoA produced.

- Succinyl-CoA, ADP, Pi, for odd chain fatty acids.

Beta oxidation of palmitic acid (Source: ´Rojinbkht via Wikimedia Commons)

If we consider as an example the complete beta oxidation of palmitic acid (palmitate), a fatty acid with 16 carbon atoms, the amount of energy produced is equivalent to more or less 129 molecules of ATP, which come from the 7 turns that it must complete. the cycle.

Regulation

The regulation of beta oxidation of fatty acids in most cells depends on energy availability, not only related to carbohydrates but also to the fatty acids themselves.

Animals control the mobilization and, therefore, the breakdown of fats through hormonal stimuli, which are at the same time controlled by molecules such as cAMP, for example.

In the liver, the main fat breakdown organ, the concentration of malonyl-CoA is extremely important for the regulation of beta oxidation; this is the first substrate involved in the fatty acid biosynthesis pathway.

When malonyl-CoA accumulates in large proportions, it promotes fatty acid biosynthesis and inhibits the mitochondrial transporter or the acyl-carnitine shuttle. When its concentration decreases, inhibition ceases and beta oxidation is activated.

References

1. Mathews, C., van Holde, K., & Ahern, K. (2000). Biochemistry (3rd ed.). San Francisco, California: Pearson.
2. Nelson, DL, & Cox, MM (2009). Lehninger Principles of Biochemistry. Omega Editions (5th ed.).
3. Rawn, JD (1998). Biochemistry. Burlington, Massachusetts: Neil Patterson Publishers.
4. Schulz, H. (1991). Beta oxidation of fatty acids. Biochimica et Biophysica Acta, 1081, 109–120.
5. Schulz, H. (1994). Regulation of Fatty Acid Oxidation in Heart. Critical Review, 165–171.
6. Schulz, H., & Kunau, W. (1987). Beta-oxidation of unsaturated fatty acids: a revised pathway. TIBS, 403-406.