- β-oxidation is a metabolic process by which fatty acids are broken down in cells to generate energy. This process occurs primarily in the mitochondria of cells for most fatty acids, though very long-chain fatty acids begin their breakdown in peroxisomes. The pathway’s name derives from the fact that oxidation occurs at the beta carbon position of the fatty acid chain.
- The process begins with the activation of fatty acids in the cytosol, where they are converted to fatty acyl-CoA by the enzyme acyl-CoA synthetase. This ATP-dependent reaction makes the fatty acid more reactive and prepares it for transport into the mitochondria. Long-chain fatty acids cannot directly cross the mitochondrial membrane and require the carnitine shuttle system, where carnitine palmitoyltransferase I (CPT1) converts fatty acyl-CoA to fatty acyl-carnitine.
- Once inside the mitochondrial matrix, the fatty acyl-carnitine is converted back to fatty acyl-CoA by carnitine palmitoyltransferase II (CPT2). The actual β-oxidation process then begins, consisting of four repeated steps: dehydrogenation, hydration, second dehydrogenation, and thiolysis. Each cycle removes two carbon atoms from the fatty acid chain in the form of acetyl-CoA.
- In the first step, acyl-CoA dehydrogenase removes two hydrogen atoms, creating a double bond between the α and β carbons. The resulting FAD is reduced to FADH2. The second step involves the addition of water across the double bond by enoyl-CoA hydratase. The third step is another dehydrogenation, this time by β-hydroxyacyl-CoA dehydrogenase, which uses NAD+ as the electron acceptor, producing NADH. The final step is catalyzed by thiolase, which cleaves the fatty acid between the α and β carbons, releasing acetyl-CoA and a fatty acyl-CoA shortened by two carbons.
- This cycle continues until the entire fatty acid chain is converted into acetyl-CoA units. For fatty acids with an odd number of carbons, the final round produces one propionyl-CoA instead of acetyl-CoA. The acetyl-CoA generated enters the citric acid cycle, while the NADH and FADH2 produced during β-oxidation feed into the electron transport chain, making fatty acid oxidation a highly efficient energy-yielding process.
- The regulation of β-oxidation is tightly controlled and integrated with other metabolic pathways. Key regulatory points include the carnitine shuttle system, particularly CPT1, which is inhibited by malonyl-CoA, a product of glucose metabolism. This coordination helps cells balance their use of glucose and fatty acids for energy production. Deficiencies in any of the enzymes involved in β-oxidation can lead to various metabolic disorders, highlighting the pathway’s importance in human health.
- The efficiency of β-oxidation makes it a crucial energy source during fasting, prolonged exercise, and in tissues like the heart, which preferentially use fatty acids for fuel. Each round of β-oxidation reduces the fatty acid by two carbons and generates FADH2, NADH, and acetyl-CoA, ultimately producing more ATP per gram than either glucose or protein metabolism.
