Alpha Oxidation- Definition, Location, Pathway, Steps, Significance
Alpha oxidation is a type of fatty acid oxidation that occurs in peroxisomes. It involves the removal of one carbon atom from the alpha position of the fatty acid chain, which is adjacent to the carboxyl group. Alpha oxidation is different from beta oxidation, which removes two carbon atoms from the beta position of the fatty acid chain, which is next to the alpha position.
Alpha oxidation is a specialized pathway that occurs in certain fatty acids that have a methyl group at the beta position. This methyl group prevents beta oxidation from taking place, as it blocks the access of the enzyme acyl-CoA dehydrogenase. Therefore, alpha oxidation is necessary to remove the methyl group and allow beta oxidation to proceed.
Alpha oxidation does not produce any ATP or NADH, unlike beta oxidation. Instead, it produces CO2 and formyl-CoA as byproducts. The main purpose of alpha oxidation is to catabolize branched-chain fatty acids and produce cerebronic acid, which is a precursor for cerebrosides and sulfatides. These are important components of the myelin sheath that surrounds nerve cells.
Alpha oxidation is also involved in the synthesis of hydroxy fatty acids, which can be further oxidized and decarboxylated to produce shorter fatty acids. This process can convert odd-chain fatty acids into even-chain fatty acids, which can undergo beta oxidation more easily.
Alpha oxidation is a rare but essential metabolic pathway that plays a role in the maintenance of nervous system function and lipid homeostasis. A defect in alpha oxidation can lead to Refsum`s disease, a genetic disorder that causes neurological and visual impairments.
Peroxisomes are small, membrane-bound organelles that are found in most eukaryotic cells. They contain various enzymes that catalyze different metabolic reactions, such as the breakdown of hydrogen peroxide, the synthesis of plasmalogens, and the oxidation of fatty acids.
One of the functions of peroxisomes is to perform alpha oxidation of branched-chain fatty acids, such as phytanic acid. Phytanic acid is a 20-carbon fatty acid that has four methyl groups at the beta-carbon position. This prevents it from undergoing beta oxidation, which is the usual pathway for fatty acid degradation in mitochondria.
Instead, phytanic acid is transported into peroxisomes by a specific carrier protein called phytanate transporter (PHYH). There, it undergoes a series of reactions that remove one carbon atom from the alpha-carbon position and produce pristanic acid, which can then enter beta oxidation in peroxisomes or mitochondria.
Alpha oxidation in peroxisomes requires oxygen and iron as cofactors. It also generates hydrogen peroxide as a by-product, which is then decomposed by catalase, another enzyme present in peroxisomes.
Alpha oxidation in peroxisomes is important for the catabolism of branched-chain fatty acids that are derived from dietary sources or from the degradation of chlorophyll. It also produces cerebronic acid, which is a precursor for the synthesis of cerebrosides and sulfatides, which are important components of myelin sheaths in nerve cells.
Defects in alpha oxidation in peroxisomes can lead to the accumulation of phytanic acid and other toxic metabolites in tissues and organs. This can cause a rare genetic disorder called Refsum`s disease, which is characterized by neurological and retinal symptoms. Refsum`s disease can be treated by dietary restriction of phytanic acid and plasmapheresis to remove excess phytanic acid from the blood.
The main substrate for alpha oxidation is phytanic acid, which is a 20-carbon, branched-chain fatty acid. Phytanic acid is not synthesized in the human body, but it is obtained from the diet. It is present in milk or derived from phytol, which is a component of chlorophyll in plants and algae. Phytol can also be found in animal fat, especially ruminant animals that feed on plants.
Phytanic acid has a methyl group (-CH3) at the beta-carbon (the second carbon from the carboxyl end), which blocks the normal beta oxidation pathway. Beta oxidation is the process of breaking down fatty acids into acetyl-CoA units that can enter the citric acid cycle and produce energy. However, beta oxidation requires the removal of two hydrogen atoms from the beta-carbon by an enzyme called acyl-CoA dehydrogenase. If the beta-carbon is methylated, this enzyme cannot act and the fatty acid cannot be degraded further.
Therefore, phytanic acid needs to undergo alpha oxidation, which is a different pathway that removes one carbon unit from the alpha-carbon (the first carbon from the carboxyl end) instead of two. This allows the fatty acid to be shortened by one carbon and then enter the beta oxidation pathway. Alpha oxidation does not produce any ATP (energy currency of the cell), but it enables the catabolism of branched-chain fatty acids that would otherwise accumulate in the body and cause toxicity.
Alpha oxidation is a metabolic pathway that involves the oxidation of fatty acids at the α-carbon, which is the second carbon atom from the carboxyl end. This pathway is different from beta oxidation, which oxidizes fatty acids at the beta-carbon, which is the third carbon atom from the carboxyl end.
Alpha oxidation occurs mainly in peroxisomes, which are small organelles that contain enzymes for various oxidative reactions. The main substrate for alpha oxidation is phytanic acid, which is a 20-carbon branched-chain fatty acid that cannot undergo beta oxidation because of the presence of a methyl group at the beta-carbon. Phytanic acid is derived from phytol, which is a component of chlorophyll in plants and algae. Phytanic acid can also be found in animal products such as milk and meat.
The pathway of alpha oxidation consists of four main steps:
- Activation of phytanic acid: Phytanic acid is first converted to phytanoyl-CoA by an enzyme called phytanoyl-CoA synthetase, which uses ATP and coenzyme A as cofactors. This step activates the fatty acid for further oxidation.
- Hydroxylation of phytanoyl-CoA: Phytanoyl-CoA is then hydroxylated at the alpha-carbon by an enzyme called phytanoyl-CoA dioxygenase, which uses iron and oxygen as cofactors. This step introduces a hydroxyl group at the alpha-carbon, forming 2-hydroxyphytanoyl-CoA.
- Removal of formyl-CoA: 2-hydroxyphytanoyl-CoA is then cleaved by an enzyme called 2-hydroxyphytanoyl-CoA lyase, which uses thiamine pyrophosphate as a cofactor. This step releases a one-carbon unit in the form of formyl-CoA, which can be further converted to formate and carbon dioxide. The remaining product is pristanal, which is a 19-carbon aldehyde.
- Oxidation of pristanal: Pristanal is then oxidized to pristanic acid by an enzyme called aldehyde dehydrogenase, which uses NAD+ as a cofactor. This step converts the aldehyde group to a carboxylic acid group, forming pristanic acid, which can then enter beta oxidation.
The overall reaction of alpha oxidation can be summarized as follows:
Phytanic acid + CoA + O2 + NAD+ -> Pristanic acid + CoA + CO2 + NADH + H+
The pathway of alpha oxidation allows the degradation of branched-chain fatty acids that cannot be metabolized by beta oxidation. It also produces cerebronic acid, which is a precursor for cerebrosides and sulfatides, which are important components of nerve tissue. Alpha oxidation is essential for human health, as defects in this pathway can cause Refsum`s disease, a rare genetic disorder that affects the nervous system and other organs.
The steps of alpha oxidation of phytanic acid are as follows :
- Activation of phytanic acid: Phytanic acid first attaches with CoA to form phytanoyl-CoA. This reaction requires ATP and is catalyzed by an acyl-CoA synthetase enzyme.
- Hydroxylation: The phytanoyl-CoA is oxidized to 2-hydroxy phytanoyl-CoA in the presence of phytanoyl-CoA dioxygenase using Fe2+ and O2. This reaction introduces a hydroxyl group at the alpha-carbon of the fatty acid chain.
- Removal of formyl CoA (CO2): The 2-hydroxy phytanoyl-CoA is cleaved by 2-hydroxyphytanoyl-CoA lyase in a TPP-dependent reaction to form pristanal and formyl-CoA. The formyl-CoA is further broken down into formate and eventually CO2. This reaction removes one carbon atom from the carboxyl end of the fatty acid chain.
- Oxidation of Pristanal: The pristanal is oxidized by aldehyde dehydrogenase to form pristanic acid. This reaction converts the aldehyde group at the end of the fatty acid chain into a carboxylic acid group.
- Beta-oxidation of pristanic acid: The pristanic acid can then undergo beta-oxidation in the peroxisomes and mitochondria, yielding acetyl-CoA and propionyl-CoA. The acetyl-CoA can enter the citric acid cycle for further oxidation, while the propionyl-CoA can be converted into succinyl-CoA and enter the citric acid cycle as well.
The main reaction involved in alpha oxidation is the conversion of phytanic acid to pristanic acid, which can then undergo beta oxidation. Phytanic acid is a 20-carbon, branched-chain fatty acid that is derived from phytol, a component of chlorophyll. Phytanic acid cannot undergo beta oxidation directly because it has a methyl group at the beta-carbon, which blocks the first step of the pathway. Therefore, it needs to be oxidized at the alpha-carbon first, which results in the removal of one carbon atom as formyl-CoA.
The reactions involved in alpha oxidation of phytanic acid are as follows:
Activation of phytanic acid: Phytanic acid is activated by an ATP-dependent reaction that attaches a CoA molecule to its carboxyl group. This forms phytanoyl-CoA, which is the substrate for the next enzyme.
Hydroxylation: Phytanoyl-CoA is hydroxylated by an enzyme called phytanoyl-CoA dioxygenase, which uses iron (Fe2+) and oxygen (O2) as cofactors. This introduces a hydroxyl group at the alpha-carbon of the fatty acid chain, forming 2-hydroxyphytanoyl-CoA.
Removal of formyl-CoA: 2-hydroxyphytanoyl-CoA is cleaved by an enzyme called 2-hydroxyphytanoyl-CoA lyase, which requires thiamine pyrophosphate (TPP) as a cofactor. This splits off a one-carbon unit as formyl-CoA from the carboxyl end of the fatty acid chain, leaving behind pristanal, a 19-carbon aldehyde.
Oxidation of pristanal: Pristanal is oxidized by an enzyme called aldehyde dehydrogenase, which uses NAD+ as a cofactor. This converts the aldehyde group to a carboxylic acid group, forming pristanic acid, which is a 19-carbon, branched-chain fatty acid.
Beta-oxidation of pristanic acid: Pristanic acid can now enter the beta-oxidation pathway in peroxisomes or mitochondria, where it is broken down into acetyl-CoA and propionyl-CoA units. Propionyl-CoA is produced when the beta-carbon of the fatty acid chain has a methyl group attached to it.
The overall equation for alpha oxidation of phytanic acid to pristanic acid is:
Phytanic acid + CoA + O2 + NAD+ -> Pristanic acid + Formyl-CoA + NADH + H+
The overall equation for beta-oxidation of pristanic acid to acetyl-CoA and propionyl-CoA is:
Pristanic acid + 7 CoA + 7 FAD + 7 NAD+ -> 8 Acetyl-CoA + Propionyl-CoA + 7 FADH2 + 7 NADH + 7 H+
Alpha oxidation is an important metabolic pathway that allows organisms to break down fatty acids with an odd number of carbon atoms. The process involves:
- The activation of the fatty acid.
- The oxidation of the alpha-carbon.
- The conversion to a dicarboxylic acid.
- The thiolysis of the dicarboxylic acid produces acetyl-CoA.
The primary significance of alpha oxidation is the production of energy. The acetyl-CoA produced by the thiolysis of the dicarboxylic acid can enter the citric acid cycle, where it is oxidized to produce ATP, the main energy currency of the cell.
Alpha oxidation is also important for the catabolism of branched-chain fatty acids, such as phytanic acid, which cannot undergo beta oxidation due to their beta-methyl branch. Phytanic acid is derived from phytol, a component of chlorophyll, and is present in animal fats and dairy products. By removing one carbon atom from the carboxyl end of phytanic acid, alpha oxidation converts it to pristanic acid, which can then undergo beta oxidation and produce propionyl-CoA.
Another significance of alpha oxidation is the production of cerebronic acid, which is a precursor for the synthesis of cerebrosides and sulfatides. Cerebrosides and sulfatides are sphingolipids that are essential for the structure and function of nerve cells and myelin sheaths. Alpha oxidation also produces odd-chain fatty acids, which can be further oxidized by beta oxidation to produce succinyl-CoA, an intermediate of the citric acid cycle.
Alpha oxidation is therefore a vital pathway for the metabolism of certain fatty acids and the biosynthesis of important lipids. It also helps to maintain the balance of carbon atoms in the fatty acid pool.
Refsum’s disease is a rare genetic disorder that affects the metabolism of phytanic acid, a branched-chain fatty acid derived from plant sources. People with Refsum’s disease have a mutation in the gene that codes for phytanoyl-CoA hydroxylase, the enzyme that catalyzes the first step of alpha oxidation in peroxisomes. As a result, they accumulate high levels of phytanic acid in their tissues and blood, which can cause damage to various organs and systems.
The symptoms of Refsum’s disease usually appear in childhood or adolescence and may include:
- Peripheral neuropathy: Damage to the nerves that control sensation and movement in the limbs, leading to numbness, tingling, pain, weakness, and loss of reflexes.
- Ataxia: Impaired coordination and balance, causing difficulty walking and performing fine motor tasks.
- Retinitis pigmentosa: Degeneration of the retina, the light-sensitive layer of the eye, causing night blindness, tunnel vision, and eventual blindness.
- Ichthyosis: Dry, scaly skin that resembles fish scales.
- Deafness: Hearing loss due to damage to the inner ear or the nerve that carries sound signals to the brain.
- Cardiomyopathy: Enlargement and weakening of the heart muscle, leading to heart failure and arrhythmias.
- Skeletal abnormalities: Short stature, scoliosis (curvature of the spine), and polydactyly (extra fingers or toes).
Refsum’s disease is diagnosed by measuring the levels of phytanic acid in blood or urine samples. Genetic testing can also confirm the presence of a mutation in the phytanoyl-CoA hydroxylase gene. The treatment for Refsum’s disease involves restricting dietary intake of phytanic acid, which is found in dairy products, meat, fish, and some vegetables. This can help lower the levels of phytanic acid in the body and prevent further damage. In some cases, plasmapheresis (a procedure that removes excess phytanic acid from the blood) may also be performed. Additionally, symptomatic treatment may include medications, physical therapy, vision aids, hearing aids, and surgery.
Refsum’s disease is a chronic and progressive condition that can affect the quality of life and life expectancy of affected individuals. However, with early diagnosis and proper management, some of the complications can be prevented or delayed. There is currently no cure for Refsum’s disease, but research is ongoing to find new ways to treat it.
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