Fatty acid oxidation (beta-oxidation)

FA Activation & Transport - The Cellular Taxi Service

• Activation (Cytoplasm): Fatty acids (FAs) are primed for oxidation by Fatty Acyl-CoA Synthetase, converting them to Fatty Acyl-CoA. This costs 2 ATP equivalents.
• Transport (Mitochondria): The carnitine shuttle transports long-chain fatty acids (LCFAs) across the inner mitochondrial membrane. 📌 CARnitine drives the CARnage of fats.

⭐ The rate-limiting enzyme is Carnitine Palmitoyltransferase I (CPT-I). It's inhibited by Malonyl-CoA (from FA synthesis), preventing simultaneous synthesis and breakdown.

β-Oxidation Pathway - The Spiral Staircase

• A recurring four-step sequence in the mitochondrial matrix that shortens fatty acyl-CoA chains by two carbons per cycle, yielding key energy precursors.

• The Four Steps (Mnemonic: 📌 "O-H-O-T"):
  • Oxidation by Acyl-CoA Dehydrogenase.
  • Hydration by Enoyl-CoA Hydratase.
  • Oxidation by β-Hydroxyacyl-CoA Dehydrogenase.
  • Thiolysis by Thiolase.

⭐ Each turn of the spiral generates 1 FADH₂, 1 NADH, and 1 Acetyl-CoA. The process repeats until the entire chain is converted to Acetyl-CoA units.

Energy Yield - Cashing in the Chips

• Each round of β-oxidation of a saturated fatty acid produces 1 FADH₂, 1 NADH, and 1 Acetyl-CoA.
• The total ATP yield for a $C_{2n}$ fatty acid can be calculated by the formula: $14n - 6$.
  • Example (Palmitate, C16; n=8): $(8 imes 10 ext{ ATP}) + (7 imes 2.5 ext{ ATP}) + (7 imes 1.5 ext{ ATP}) - 2 ext{ ATP} = extbf{106}$ ATP net yield.

⭐ Odd-chain fatty acids produce propionyl-CoA in the final round, which can be converted to succinyl-CoA and enter the TCA cycle, making it glucogenic.

Regulation & Odd Chains - Rules & Exceptions

• Rate-Limiting Step: Carnitine Palmitoyltransferase I (CPT-I).

  • Inhibition: Malonyl-CoA (from FA synthesis) allosterically inhibits CPT-I.
  • Hormonal Control: ↑Insulin/glucagon ratio → ↑Malonyl-CoA → ↓β-oxidation.

• Odd-Chain Fatty Acids: Final product is Propionyl-CoA (3C), not Acetyl-CoA.

⭐ Vitamin B12 deficiency causes methylmalonic acidemia & aciduria, leading to neurological deficits from abnormal myelin synthesis.

Clinical Correlates - When the Engine Fails

• Defects in β-oxidation impair energy production during fasting, leading to a classic triad:
  • Hypoketotic hypoglycemia: ↓ glucose with inappropriately low ketones.
  • Hepatomegaly and liver dysfunction (↑ LFTs).
  • Skeletal myopathy, rhabdomyolysis, and cardiomyopathy.
• Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency:
  • Most common defect; presents at 2 months to 2 years.
  • Triggers: fasting, infection (e.g., gastroenteritis).
  • Labs: ↑ C8-C10 acylcarnitines, dicarboxylic aciduria.
• Carnitine Deficiency:
  • Impairs long-chain fatty acid transport into mitochondria.
  • 📌 CARnitine = CARnage of muscle & heart (weakness, cardiomyopathy).

⭐ During fasting, lack of acetyl-CoA from β-oxidation stalls both ketogenesis and gluconeogenesis (pyruvate carboxylase needs acetyl-CoA), causing the hallmark hypoketotic hypoglycemia.

High-Yield Points - ⚡ Biggest Takeaways

• Beta-oxidation occurs in the mitochondria, breaking down fatty acids into acetyl-CoA.
• The carnitine shuttle (CPT1) is the rate-limiting step for transporting long-chain fatty acids into the mitochondria.
• MCAD deficiency is the most common genetic defect, presenting with hypoketotic hypoglycemia and lethargy.
• Each round yields 1 FADH₂, 1 NADH, and 1 acetyl-CoA.
• Inhibited by malonyl-CoA and a high NADH/NAD⁺ ratio.
• Odd-chain fatty acids yield propionyl-CoA, requiring biotin and B12 for metabolism.
• VLCFAs are initially oxidized in peroxisomes.