Omega oxidation (ω-oxidation) of fatty acid

Omega oxidation (ω-oxidation) is a process of fatty acid metabolism that occurs in some animals and plants. It involves the introduction of a hydroxyl group at the terminal carbon atom (omega carbon) of a fatty acid chain, followed by oxidation to form a dicarboxylic acid.

In vertebrates, the enzymes for ω-oxidation are located in the smooth endoplasmic reticulum (ER) of liver and kidney cells. The smooth ER is a membrane-bound organelle that contains various enzymes involved in lipid synthesis and detoxification. The location of ω-oxidation in the smooth ER distinguishes it from β-oxidation, which occurs in the mitochondria.

The smooth ER is also the site of cytochrome P450 enzymes, which are involved in the first step of ω-oxidation. Cytochrome P450 enzymes are a family of heme-containing proteins that catalyze the insertion of oxygen into organic molecules. They use molecular oxygen (O2) and NADPH as substrates and produce water (H2O) as a byproduct. Cytochrome P450 enzymes are responsible for the hydroxylation of the omega carbon of fatty acids, as well as many other reactions involved in drug metabolism and biosynthesis of hormones and cholesterol.

The location of ω-oxidation in the smooth ER allows it to act on medium to long chain fatty acids (10-12 carbon atoms), which are more abundant in the cytosol than in the mitochondria. The products of ω-oxidation can then enter the mitochondria and undergo β-oxidation by the normal route, or be used for other metabolic pathways. For example, some dicarboxylic acids can enter the citric acid cycle as succinyl-CoA, or be used for gluconeogenesis under conditions of starvation and diabetes.

Omega oxidation is a subsidiary pathway for fatty acid degradation that can compensate for impaired β-oxidation. It also plays important roles in the production of insect pheromones, plant biopolyesters, and signaling molecules.

Omega oxidation (ω-oxidation) of fatty acids is a metabolic pathway that involves the oxidation of the terminal carbon atom (ω-carbon) of fatty acids. The substrate for this pathway is usually medium to long chain fatty acids, which have 10 to 12 carbon atoms in their structure. These fatty acids are derived from dietary sources or from endogenous synthesis in the liver.

Medium to long chain fatty acids are transported into the cells by specific membrane proteins called fatty acid transporters (FATs). Once inside the cells, they are activated by coenzyme A (CoA) and then transferred to the smooth endoplasmic reticulum (ER), where the enzymes for ω-oxidation are located. The activated fatty acids can also undergo β-oxidation in the mitochondria, which is the main pathway for fatty acid degradation. However, when β-oxidation is impaired or overloaded, ω-oxidation becomes an alternative route for fatty acid catabolism.

The ω-oxidation pathway can also act on other types of fatty acids, such as branched-chain fatty acids, very long chain fatty acids, and polyunsaturated fatty acids. However, these substrates are less common and require additional enzymes for their oxidation. Therefore, medium to long chain fatty acids are considered the primary substrate for ω-oxidation of fatty acids.

The final product of omega oxidation of fatty acids is a dicarboxylic acid, which is a molecule that has two carboxyl groups (-COOH) at each end. A carboxyl group is an organic functional group that consists of a carbon atom double-bonded to an oxygen atom and single-bonded to a hydroxyl group (-OH). Carboxyl groups are acidic and can donate a proton (H+) to a base.

Dicarboxylic acids are also known as dicarboxylates or alpha-omega dicarboxylic acids (AODAs), because they have carboxyl groups at the alpha and omega positions of the carbon chain. The alpha position is the first carbon atom attached to the carboxyl group, and the omega position is the last carbon atom attached to the carboxyl group.

The length and structure of the dicarboxylic acid depend on the original fatty acid that underwent omega oxidation. For example, if the fatty acid had 10 carbon atoms, then the dicarboxylic acid will have 11 carbon atoms. If the fatty acid had a double bond between the 9th and 10th carbon atoms, then the dicarboxylic acid will have a double bond between the 10th and 11th carbon atoms.

Some examples of dicarboxylic acids produced by omega oxidation are:

• Sebacic acid: This is a 10-carbon dicarboxylic acid that is derived from decanoic acid, a 10-carbon saturated fatty acid. Sebacic acid is used as an intermediate in the production of nylon and other synthetic polymers.
• Suberic acid: This is an 8-carbon dicarboxylic acid that is derived from octanoic acid, an 8-carbon saturated fatty acid. Suberic acid is used as a precursor for polyesters and plasticizers.
• Adipic acid: This is a 6-carbon dicarboxylic acid that is derived from hexanoic acid, a 6-carbon saturated fatty acid. Adipic acid is one of the most important industrial chemicals, as it is used to make nylon 6,6 and other polyamides.
• Succinic acid: This is a 4-carbon dicarboxylic acid that is derived from butanoic acid, a 4-carbon saturated fatty acid. Succinic acid is involved in many metabolic pathways, such as the citric acid cycle and gluconeogenesis. It can also be used as a food additive, a solvent, and a precursor for various chemicals.

Dicarboxylic acids can be further metabolized by various pathways in different organisms. For example, some bacteria can use dicarboxylic acids as carbon sources by breaking them down into acetyl-CoA units. Some plants can use dicarboxylic acids to synthesize biopolymers such as polyhydroxyalkanoates (PHAs), which are biodegradable plastics. Some animals can use dicarboxylic acids to regulate their body temperature by increasing their heat production.

Dicarboxylic acids are important biomolecules that have diverse functions and applications in nature and industry. They are the end products of omega oxidation of fatty acids, which is a minor but significant pathway of fatty acid metabolism.

The ω-oxidation of fatty acids involves three main steps: hydroxylation, oxidation, and β-oxidation. The following diagram illustrates these steps:

Hydroxylation

The first step introduces a hydroxyl group (-OH) onto the ω-carbon, which is the last carbon atom in the fatty acid chain. The oxygen for this group comes from molecular oxygen (O2) in a complex reaction that involves cytochrome P450 and the electron donor NADPH. Cytochrome P450 is a family of enzymes that catalyze various oxidation reactions in the body. NADPH is a coenzyme that provides reducing power for these reactions. Reactions of this type are catalyzed by mixed function oxidases, which are enzymes that can transfer one atom of oxygen to a substrate and another to water.

The hydroxylation reaction can be written as:

R-CH2-CH2-COOH + O2 + NADPH + H+ → R-CH2-CH(OH)-COOH + H2O + NADP+

where R is the rest of the fatty acid chain.

Oxidation

The second step involves two consecutive oxidation reactions that convert the hydroxyl group to an aldehyde group (-CHO) and then to a carboxylic acid group (-COOH). These reactions are catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, respectively. These are enzymes that use NAD+ as an electron acceptor and produce NADH as a byproduct. The oxidation reactions can be written as:

R-CH2-CH(OH)-COOH + NAD+ → R-CH2-CHO-COOH + NADH + H+

R-CH2-CHO-COOH + NAD+ + H2O → R-COOH-CH2-COOH + NADH + H+

The final product of these reactions is a dicarboxylic acid, which is a fatty acid with a carboxyl group at each end.

β-oxidation

The third step is the same as the normal β-oxidation pathway that occurs in the mitochondria. The dicarboxylic acid can enter the mitochondrion and undergo β-oxidation by attaching either end to coenzyme A (CoA). CoA is a molecule that helps transport fatty acids into the mitochondria and also participates in their breakdown. In each pass through the β-oxidation pathway, the dicarboxylic acid loses two carbon atoms as acetyl-CoA, which can enter the citric acid cycle and produce energy. The remaining dicarboxylic acid can undergo further β-oxidation until it is completely degraded.

The β-oxidation reaction can be written as:

R-COOH-CH2-COOH + CoA → R-COOH + CH3-CO-CoA

where R is the rest of the dicarboxylic acid chain.

Omega oxidation (ω-oxidation) of fatty acids is a process that involves the oxidation of the carbon atom farthest from the carboxyl group of the fatty acid chain. It is an alternative pathway to beta oxidation that occurs in the smooth endoplasmic reticulum of liver and kidney cells. Omega oxidation has several biological functions and implications for various organisms and conditions. Some of them are:

• It is a subsidiary pathway for beta oxidation of fatty acids when beta oxidation is blocked. For example, when there is a deficiency of carnitine or acyl-CoA dehydrogenase, omega oxidation can provide an alternative route for fatty acid degradation and energy production.
• It serves to provide succinyl-CoA for the citric acid cycle and for gluconeogenesis under conditions of starvation and diabetes. Succinyl-CoA is an intermediate of the citric acid cycle that can also be converted to malate and then to glucose by gluconeogenesis. Thus, omega oxidation can help maintain blood glucose levels and prevent ketoacidosis.
• It plays crucial roles in the production of insect pheromones and in the formation of biopolyesters of higher plants. Insect pheromones are chemical signals that regulate the behavior and reproduction of insects. For example, omega oxidation of fatty acids is involved in the biosynthesis of sex pheromones of honeybees. Biopolyesters are natural polymers that are synthesized by plants and bacteria. For example, omega oxidation of fatty acids is involved in the formation of polyhydroxyalkanoates, which are biodegradable plastics produced by some bacteria and plants.
• It modifies and inactivates various fatty acid metabolites that are involved in regulating inflammatory, vascular, and other responses in animals and humans. For example, omega oxidation of arachidonic acid produces 20-hydroxyeicosatetraenoic acid (20-HETE), which has various effects on blood vessels, kidneys, and cancer cells. Omega oxidation also reduces the activity of leukotrienes, prostaglandins, and other eicosanoids that are derived from arachidonic acid and mediate inflammation, pain, fever, and other responses.

Omega oxidation of fatty acids is therefore a significant metabolic pathway that has diverse biological implications for different organisms and conditions.

The activity of ω-oxidation enzymes is influenced by various factors, such as the availability of substrates, hormones, and dietary components. Some examples are:

• The expression of CYP4A and CYP4F enzymes that catalyze the first step of ω-oxidation is induced by peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that regulate lipid metabolism and inflammation.
• The levels of CYP4A and CYP4F enzymes are also modulated by glucocorticoids, thyroid hormones, and insulin.
• The ω-oxidation of arachidonic acid to 20-HETE, a potent vasoconstrictor and pro-inflammatory mediator, is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen.
• The ω-oxidation of fatty acids is enhanced by a high-fat diet and reduced by a low-fat diet.

The activity of ω-oxidation enzymes is influenced by various factors, such as the availability of substrates, hormones, and dietary components. For example, ω-oxidation of fatty acids is increased by high-fat diets, fasting, diabetes, and glucagon, and decreased by insulin and ethanol. The expression of cytochrome P450 enzymes involved in ω-oxidation is also regulated by transcription factors such as peroxisome proliferator-activated receptors (PPARs), which are activated by fatty acids and their derivatives. PPARs modulate the expression of genes involved in lipid metabolism, inflammation, and cellular differentiation. Moreover, the products of ω-oxidation can act as feedback inhibitors of the pathway by inhibiting the activity or expression of ω-oxidation enzymes. For instance, 20-HETE inhibits the activity of CYP4A11 and CYP4F2 in human liver microsomes. Thus, ω-oxidation of fatty acids is a tightly regulated process that responds to the metabolic needs and physiological conditions of the organism.

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