β-Oxidation of Fatty Acids (Even-Number Carbon Chains)
1. Overview
- β-oxidation is the major pathway for the breakdown of fatty acids.
- It occurs in the mitochondrial matrix.
- The pathway removes 2-carbon fragments at a time from the carboxyl end of fatty acids, forming acetyl-CoA.
- It provides a large amount of ATP, especially during fasting, exercise, and starvation.
2. Activation of Fatty Acids (Before entering mitochondria)
- Free fatty acids in the cytosol must first be activated to fatty acyl-CoA.
- This activation occurs in the cytosol and is catalyzed by:
- Fatty acyl-CoA synthetase (Thiokinase).
- The reaction uses ATP, which is converted to AMP + PPi.
- This is equivalent to using 2 ATP (because ATP → AMP consumes two high-energy bonds).
Outcome: Fatty acid + CoA → Fatty acyl-CoA
3. Transport of Activated Fatty Acids Into Mitochondria
- Long-chain fatty acyl-CoA cannot enter mitochondria directly.
- Transport requires the Carnitine Shuttle System:
Step 1: Formation of Acyl-Carnitine
- Enzyme: Carnitine acyltransferase I (CAT-I / CPT-I) on outer mitochondrial membrane.
- Fatty acyl-CoA + Carnitine → Acyl-carnitine.
Step 2: Transport Across Inner Membrane
- Transport protein: Carnitine–acylcarnitine translocase carries acyl-carnitine into matrix.
Step 3: Regeneration of Fatty acyl-CoA
- Enzyme: Carnitine acyltransferase II (CAT-II / CPT-II) in the matrix.
- Acyl-carnitine → Fatty acyl-CoA + Carnitine (carnitine re-cycled out).
- Regulation here is critical:
- Malonyl-CoA inhibits CPT-I, preventing β-oxidation during fatty acid synthesis.
4. β-Oxidation Reactions (Cycle Steps)
Each cycle removes 2 carbons from the fatty acyl-CoA chain.
Each cycle has 4 steps:
- Oxidation
- Enzyme: Acyl-CoA dehydrogenase
- Forms FADH₂
- Produces: Trans-Δ²-enoyl-CoA
- Hydration
- Enzyme: Enoyl-CoA hydratase
- Adds H₂O
- Produces: L-β-Hydroxyacyl-CoA
- Oxidation
- Enzyme: β-Hydroxyacyl-CoA dehydrogenase
- Forms NADH
- Produces: β-Ketoacyl-CoA
- Cleavage (Thiolysis)
- Enzyme: Thiolase
- Removes acetyl-CoA
- Produces a shorter fatty acyl-CoA (by 2 carbons)
- This shortened fatty acyl-CoA re-enters the cycle.
5. Regulation of β-Oxidation
- Carnitine shuttle is the main regulatory point.
- Inhibited by Malonyl-CoA → prevents simultaneous fatty acid synthesis & breakdown.
- Energy state:
- High ATP/NADH → inhibits β-oxidation (negative feedback).
- Hormonal control:
- Glucagon and epinephrine increase lipolysis → ↑ β-oxidation.
- Insulin decreases lipolysis → ↓ β-oxidation.
6. Metabolic and Energy Yield (Even-Carbon Example)
Let’s consider Palmitic Acid (16 carbons) as the classical example.
- Number of β-oxidation cycles:
- For a fatty acid with n carbons:
- (n/2) – 1 cycles
- Palmitate (16 carbons) → (16/2) – 1 = 7 cycles
- Products produced:
- Each cycle yields:
- 1 FADH₂
- 1 NADH
- 1 acetyl-CoA (except final cleavage gives 2 acetyl-CoA)
- Total acetyl-CoA from palmitate:
- 16 carbons → 8 acetyl-CoA
- ATP Yield:
- Each FADH₂ → 1.5 ATP