Fatty Acid Oxidation Pathways

Introduction to Beta-Oxidation

Beta-oxidation is the metabolic process by which fatty acids are broken down in the mitochondria to generate acetyl-CoA, which subsequently enters the citric acid cycle for energy production. This pathway is particularly active during periods of carbohydrate scarcity and is essential for mobilising energy from stored lipids.

Fatty Acid Activation

Before fatty acids can undergo oxidation, they must first be activated to acyl-CoA compounds. This activation occurs in the outer mitochondrial membrane and is catalysed by acyl-CoA synthetase (also called fatty acid thiokinase). The reaction requires ATP and produces acyl-CoA and AMP plus pyrophosphate (PPi).

Carnitine Shuttle System

Acyl-CoA molecules cannot directly cross the inner mitochondrial membrane due to their hydrophilic phosphate groups. The carnitine shuttle system facilitates their entry into the mitochondrial matrix where oxidation occurs. Carnitine palmitoyltransferase I (CPT I) transfers the acyl group from CoA to carnitine, creating acyl-carnitine. After translocation across the inner membrane by carnitine-acylcarnitine translocase, carnitine palmitoyltransferase II (CPT II) regenerates acyl-CoA inside the matrix.

The Beta-Oxidation Cycle

The beta-oxidation cycle consists of four sequential enzymatic reactions, which are repeated until the fatty acid is completely oxidised:

Step 1 - Oxidation by Acyl-CoA Dehydrogenase: The enzyme removes electrons from the acyl-CoA, forming a double bond between the alpha and beta carbons. The electrons are transferred to flavin adenine dinucleotide (FAD), generating FADH2.

Step 2 - Hydration by Enoyl-CoA Hydratase: Water is added across the double bond created in the first reaction, producing a hydroxyl group at the beta carbon.

Step 3 - Oxidation by 3-Hydroxyacyl-CoA Dehydrogenase: The hydroxyl group is oxidised to a ketone group, with electrons transferred to NAD+, generating NADH.

Step 4 - Cleavage by Thiophorase (Beta-Ketothiolase): The acyl-CoA molecule is cleaved between the alpha and beta carbons by nucleophilic attack of Coenzyme A, releasing acetyl-CoA and producing an acyl-CoA that is two carbons shorter.

Energy Yield from Beta-Oxidation

Each cycle of beta-oxidation generates 1 FADH2 and 1 NADH. A fatty acid with 16 carbons (palmitate) undergoes 7 cycles of beta-oxidation, producing 7 FADH2, 7 NADH, and 8 acetyl-CoA molecules. When these reducing equivalents and acetyl-CoA enter oxidative metabolism, they generate substantial ATP. Each FADH2 yields approximately 1.5 ATP, each NADH yields approximately 2.5 ATP, and each acetyl-CoA entering the citric acid cycle yields approximately 10 ATP.

Regulation of Beta-Oxidation

Beta-oxidation is regulated through several mechanisms including hormonal signals, allosteric regulation, and substrate availability. Carnitine palmitoyltransferase I (CPT I) is the key regulatory enzyme and is inhibited by malonyl-CoA, the first committed intermediate in fatty acid synthesis. This ensures that fatty acid oxidation and synthesis do not occur simultaneously.

During fasting states and low carbohydrate availability, malonyl-CoA levels decrease, allowing CPT I to be active and promoting fatty acid oxidation. Conversely, after carbohydrate-rich meals, malonyl-CoA levels increase, inhibiting CPT I and preventing beta-oxidation while fatty acid synthesis proceeds.

Ketone Body Production

When beta-oxidation occurs at high rates, acetyl-CoA concentration exceeds the capacity of the citric acid cycle to utilise it. Under these conditions, acetyl-CoA is converted to ketone bodies (acetoacetate, beta-hydroxybutyrate, and acetone) in the liver. Ketone bodies serve as alternative energy substrates for peripheral tissues, particularly during prolonged fasting or very low carbohydrate diets.

Fatty Acid Chain Length and Oxidation

Most dietary fatty acids are even-chained, producing acetyl-CoA exclusively. Odd-chained fatty acids generate acetyl-CoA from complete oxidation plus one propionyl-CoA molecule, which is converted to succinyl-CoA and enters the citric acid cycle as an anaplerotic substrate.

Unsaturated Fatty Acid Oxidation

Unsaturated fatty acids require additional enzymatic steps beyond the standard beta-oxidation cycle. Double bonds in unsaturated fatty acids are rearranged or isomerised before normal beta-oxidation can proceed. These auxiliary steps require specific isomerases and reductases but do not substantially alter the overall energy yield of oxidation.

Metabolic Variations and Individual Differences

The capacity for fatty acid oxidation varies between individuals based on mitochondrial enzyme expression, carnitine availability, physical activity levels, dietary composition history, and genetic factors. Tissues with high metabolic demand and abundant mitochondria (such as cardiac muscle) are particularly adept at oxidising fatty acids for energy.

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