Omega Oxidation of Fatty Acids: Enzymes, Steps, Reactions

Fatty acids are essential components of our diet and play crucial roles in various biological processes. They serve as a major source of energy and are involved in the synthesis of important molecules such as phospholipids and signaling molecules. Fatty acids are long-chain hydrocarbons with a carboxyl group at one end. They can be categorized into saturated fatty acids, which lack double bonds, and unsaturated fatty acids, which contain one or more double bonds.

Pathways of Fatty Acid Oxidation

• The breakdown of fatty acids to generate energy occurs through a process known as fatty acid oxidation. 
• It takes place primarily in the mitochondria of cells and involves several interconnected pathways. 
• The most well-known pathway is called beta-oxidation, which occurs in the cytosol and mitochondria and involves the stepwise cleavage of fatty acids into two-carbon units called acetyl-CoA.
• This process generates ATP, NADH, and FADH2, which can be utilized in cellular respiration to produce energy.

What is Omega Oxidation?

Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. Omega oxidation is an alternative pathway to beta-oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon (the carbon most distant from the carboxyl group of the fatty acid).

• The ω (omega)-carbon (the methyl carbon) of fatty acids is oxidized to a carboxyl group in the endoplasmic reticulum.
• The process is usually a minor catabolic pathway for medium-chain fatty acids (10-12 carbon atoms). Still, it becomes more critical when β oxidation is defective (because of mutation or a carnitine deficiency).

Location of Omega Oxidation

• Apart from beta-oxidation, there is another pathway known as omega oxidation that occurs in the endoplasmic reticulum of cells. 
• Omega oxidation is responsible for the metabolism of fatty acids with a methyl group at the omega (ω) carbon, which is the carbon farthest away from the carboxyl group. 
• This pathway is particularly important for the breakdown of long-chain fatty acids that cannot enter the mitochondria for beta-oxidation due to their size or location within cellular compartments.

ω-Oxidation of Fatty Acids Reactions

• The omega oxidation pathway involves several steps, each catalyzed by specific enzymes. 
• The first step is the hydroxylation of the fatty acid at the omega carbon, which is mediated by enzymes called cytochrome P450 monooxygenases. 
• This reaction introduces a hydroxyl group (-OH) at the omega carbon, resulting in the formation of a hydroxy fatty acid.
• The hydroxy fatty acid is then further oxidized to a keto fatty acid by the action of hydroxy acyl-CoA dehydrogenase. 
• This enzyme catalyzes the removal of two hydrogen atoms from the hydroxyl group, resulting in the formation of a double bond between the carbon carrying the hydroxyl group and the adjacent carbon.
• The keto fatty acid is then cleaved into two fragments by the enzyme thiolase, similar to the cleavage that occurs during beta-oxidation. 
• This step generates a dicarboxylic acid, which can be further metabolized through various pathways depending on the specific cellular requirements.

Steps of Omega Oxidation

1. Hydroxylation

• The fatty acid is hydroxylated at the omega carbon by cytochrome P450 monooxygenases, forming a hydroxy fatty acid.
• The first step in omega oxidation is the hydroxylation of the fatty acid at the omega carbon. 
• This reaction is catalyzed by cytochrome P450 monooxygenases, which are enzymes located in the endoplasmic reticulum. 
• The hydroxylation reaction requires molecular oxygen (O₂) and NADPH as a source of reducing equivalents. 
• The hydroxyl group (-OH) is introduced at the omega carbon, resulting in the formation of a hydroxy fatty acid.

Reaction : Fatty acid + NADPH + O₂ + Cytochrome P450 monooxygenase → Hydroxy fatty acid + NADP⁺ + H₂O

2. Oxidation 

• Hydroxyacyl-CoA dehydrogenase oxidizes the hydroxy fatty acid to a keto fatty acid by removing two hydrogen atoms from the hydroxyl group.
• After the hydroxylation step, the hydroxy fatty acid undergoes further oxidation. The enzyme hydroxy acyl-CoA dehydrogenase catalyzes this reaction. 
• It removes two hydrogen atoms from the hydroxyl group, resulting in the formation of a double bond between the carbon carrying the hydroxyl group and the adjacent carbon. 
• The enzyme utilizes FAD (flavin adenine dinucleotide) as a cofactor and generates FADH₂ in the process.

Reaction :Hydroxy fatty acid + FAD → Keto fatty acid + FADH₂

3. Cleavage

• The thiolase enzyme catalyzes the cleavage of the keto-fatty acid into two fragments, resulting in the formation of a dicarboxylic acid. 
• The next step is the cleavage of the keto-fatty acid into two fragments. 
• This cleavage reaction is catalyzed by the enzyme thiolase, which is also involved in the beta-oxidation pathway. 
• Thiolase breaks the keto fatty acid into two parts: a dicarboxylic acid and an acyl-CoA molecule. 
• The acyl-CoA can enter the beta-oxidation pathway for further energy production, while the dicarboxylic acid continues through the omega oxidation pathway.

Reaction: Keto fatty acid + CoA-SH → Dicarboxylic acid + Acyl-CoA

4. Further Metabolism 

• The dicarboxylic acid generated from the cleavage step can undergo further metabolism depending on the cellular requirements. 
• It can be converted into acyl-CoA, which can enter the beta-oxidation pathway for further energy production. 
• Alternatively, the dicarboxylic acid can be converted into other metabolites through various enzymatic reactions.
• The conversion involves the activation of the dicarboxylic acid to form acyl-CoA, a process catalyzed by acyl-CoA synthetase enzymes.

Significance of Omega Oxidation

Omega oxidation functions as an alternative pathway for breaking down fatty acids that are unable to undergo beta-oxidation. It enables the metabolism of long-chain fatty acids that cannot cross the mitochondrial membrane due to their size or location within cellular compartments. This pathway ensures that fatty acids can be fully utilized for energy production and other metabolic processes.

Detoxification Of Xenobiotics Compounds

Additionally, omega oxidation plays a vital role in the detoxification of xenobiotic compounds, including certain drugs and environmental toxins.

• These compounds are typically hydrophobic and require enzymatic modifications to become more water-soluble for elimination. 
• Omega oxidation contributes to the hydroxylation and subsequent modification of these xenobiotics, facilitating their removal from the body. 
• Omega oxidation is especially crucial in tissues with a high capacity for detoxification and xenobiotic clearance. 
• The hydroxylation step in omega oxidation is involved in metabolizing various drugs and environmental toxins, aiding in their elimination from the body. 
• This pathway enables the conversion of hydrophobic compounds into more water-soluble forms, which can be excreted through urine or bile.

Long-Chain Fatty Acids

• Moreover, omega oxidation is essential for metabolizing long-chain fatty acids that cannot undergo beta-oxidation due to their size or location within cellular compartments.  
• It ensures that these fatty acids are fully utilized for energy production and other metabolic processes. 
• This becomes particularly significant during prolonged fasting or when the body’s energy demands are elevated.

Furthermore, defects in omega oxidation can result in various metabolic disorders, including Zellweger syndrome. This disorder is characterized by impaired peroxisome function, the cellular organelles responsible for omega oxidation. As a consequence, very long-chain fatty acids accumulate, leading to severe neurological and developmental abnormalities.

Conclusion

In conclusion, omega oxidation is an important pathway for the metabolism of fatty acids with a methyl group at the omega carbon. It takes place in the endoplasmic reticulum and involves several enzymatic steps, including hydroxylation, oxidation, cleavage, and further metabolism.

Omega oxidation allows the breakdown of long-chain fatty acids that cannot undergo beta-oxidation, ensuring their full utilization for energy production and other metabolic processes.

Furthermore, this pathway plays a crucial role in the detoxification of xenobiotic compounds. Defects in omega oxidation can result in metabolic disorders and highlight the significance of this pathway in maintaining proper cellular function.

References

1. Omega Oxidation of Fatty Acids – https://byjus.com/neet/omega-oxidation-of-fatty-acids/
2. Miura, Yoshiro. “The biological significance of ω-oxidation of fatty acids.” Proceedings of the Japan Academy, Series B 89.8 (2013): 370-382.
3. Omega oxidation – http://bcas.du.ac.in/wp-content/uploads/2020/04/BIOCHEM-OMEGA-OXIDATION-NOTES-1.pdf
4. Fatty Acid Omega Oxidation – https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/fatty-acid-omega-oxidation
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