Fatty Acid Oxidation

Overview

1. Energy Production: Discussion of energy produced through fatty acid oxidation.
2. Mnemonic: Remembering the beta oxidative pathways.
3. Specific Pathways: Beta oxidation in peroxisomes and odd-chain fatty acids.

Beta Oxidation Pathway

Initial Steps

• Palmitoleic Acid: 16 carbon fatty acid.
• Conversion: Palmitoleic acid → Palmitoyl CoA via Fatty acyl CoA synthetase (Uses ATP to convert ATP → ADP + Pi).
• Transport: Palmitoyl CoA transported into the mitochondrial matrix via CAT1/Carnitine acyltransferase 1.
  • Palmitoyl CoA + Carnitine → Palmitoyl Carnitine (releases CoA).
• Inside Mitochondria: CAT2/CPT2 recycles carnitine and adds CoA → Palmitoyl CoA.

Mnemonic: OHOT (Oxidation, Hydration, Oxidation, Thiolysis)

1. Oxidation: FAD → FADH2 (First step, trans-delta-2-enoyl CoA formation).
2. Hydration: Addition of H2O → beta-hydroxy-acyl CoA.
3. Oxidation: NAD+ → NADH, formation of beta-keto acyl CoA (ketone).
4. Thiolysis: Thiolase enzyme splits the bond between alpha and beta carbon, producing a shorter fatty acyl CoA (e.g., 16 → 14 carbons) and acetyl-CoA.

Energy Calculation from Palmitate (16-carbons)

• Acetyl CoA: 8 acetyl CoAs (from 16-carbon fatty acid).
  • Krebs Cycle Yield: Per Acetyl CoA: 3 NADH, 1 FADH2, 1 ATP.
  • Total from 8 Acetyl CoAs: 24 NADH, 8 FADH2, 8 ATP.
• Beta Oxidation Yield: 7 cycles (because each produces 1 Acetyl CoA after the split).
  • Total: 7 NADH, 7 FADH2.
• Total Energy Production: 131 ATP net (after subtracting 1 ATP used in fatty acid activation).

Rounded ATP Calculation

• With NADH = 2.5 ATP & FADH2 = 1.5 ATP: ~108 ATP (net around 107 after activation subtraction).

Odd-Chain Fatty Acid Oxidation

• Odd-Chain Fatty Acids: Results in propionyl-CoA (3-carbon fragment) instead of just acetyl-CoA.
• Propionyl-CoA Conversion:
  • Carboxylation: Propionyl-CoA → Methylmalonyl-CoA (requires ATP, bicarbonate, and biotin).
  • Isomerization: Methylmalonyl-CoA → Succinyl-CoA (requires vitamin B12).
• Succinyl-CoA Pathways:
  • Entry to Krebs cycle to produce ATP.
  • Conversion to malate for gluconeogenesis (PEP → glucose).
  • Precursor for heme synthesis (porphyrins).
• Related Disorders: Pernicious anemia (due to lack of vitamin B12 affecting this pathway).

Peroxisomal Fatty Acid Oxidation

• Differences: First step uses oxygen to form H2O2 instead of transferring electrons to the electron transport chain.
  • Catalase Role: Breaks down H2O2 to prevent damage.
• Disorders:
  • MCAD Deficiency: Medium-Chain Acyl-CoA Dehydrogenase deficiency causing hypoglycemia, lipid accumulation in the liver, vomiting, sleepiness, coma. Treatment involves high-carb diet.
  • X-linked Adrenoleukodystrophy: Transporter deficiency leading to high blood fatty acids, visual and behavioral disturbances, coma, and potential death.
  • Zellweger Syndrome: Defective peroxisome biogenesis leading to multiple systemic issues.

Summary

• Reviewed beta oxidation pathway activation, transport, and energy tally from a 16-carbon fatty acid.
• Discussed oxidation of odd-chain fatty acids and roles of propionyl-CoA, biotin, and vitamin B12.
• Peroxisomal fatty acid oxidation compared to mitochondrial oxidation.
• Highlighted metabolic disorders associated with fatty acid oxidation deficiencies.