Beta-oxidation pathway
Beta-Oxidation of Fatty Acids
Beta-oxidation is the primary catabolic pathway for breaking down fatty acids into acetyl-CoA units, generating energy through NADH and FADH2 for the electron transport chain. This process occurs mainly in the mitochondrial matrix and provides a key energy source during fasting or high-demand states like exercise. Each cycle shortens the fatty acyl chain by two carbons, repeating until the entire chain converts to acetyl-CoA.
Activation and Transport
Fatty acids from lipolysis first undergo activation in the cytosol by acyl-CoA synthetases, forming fatty acyl-CoA with ATP hydrolysis to AMP and pyrophosphate. The acyl-CoA then conjugates with carnitine via carnitine palmitoyltransferase I (CPT-I) on the outer mitochondrial membrane, forming acylcarnitine for transport across the inner membrane by carnitine-acylcarnitine translocase. Inside the matrix, CPT-II regenerates acyl-CoA and free carnitine, priming the chain for oxidation.
Core Beta-Oxidation Cycle
Step 1: Dehydrogenation
Acyl-CoA dehydrogenase catalyzes the removal of two hydrogens from carbons 2 (alpha) and 3 (beta), forming a trans-Δ²-enoyl-CoA and reducing FAD to FADH₂. This flavin-dependent step initiates the cycle and varies by chain length with specific isozymes.
Step 2: Hydration
Enoyl-CoA hydratase adds water across the double bond in an anti-Markovnikov fashion, yielding L-3-hydroxyacyl-CoA with a hydroxyl group at the beta carbon. This reversible reaction prepares the substrate for further oxidation.
Step 3: Second Dehydrogenation
3-Hydroxyacyl-CoA dehydrogenase oxidizes the beta-hydroxyl to a keto group, producing 3-ketoacyl-CoA and NADH + H⁺ via NAD⁺. This NAD-dependent step generates reducing equivalents for ATP production.
Step 4: Thiolysis
Beta-ketoacyl-CoA thiolase cleaves the beta-ketoacyl-CoA between carbons 2 and 3 using CoA-SH, releasing acetyl-CoA and a shortened acyl-CoA that re-enters the cycle. For an even-chain fatty acid like palmitate (C16), seven cycles yield eight acetyl-CoA molecules.
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Energy Yield and Regulation
Complete oxidation of one palmitoyl-CoA produces 108 ATP equivalents: 7 FADH₂ (14 ATP), 7 NADH (21 ATP), 8 acetyl-CoA (80 ATP after TCA cycle), minus 2 ATP for activation. Regulation occurs via malonyl-CoA inhibition of CPT-I during fed states and allosteric control of dehydrogenases. Defects in this pathway underlie disorders like MCAD deficiency.