Energy Metabolism - Part 5: Beta-oxidation Reactions

Overview

• Beta-oxidation degrades activated fatty acids to form acetyl-CoA.
• Cleavage occurs at the beta-carbon (C3) in four reaction steps.
• Molecule reactivity near the carboxylic acid group enables breakdown at the head.

Reaction Steps

Step 1: Formation of Delta-2-trans-enoyl-CoA

• Process: Single bond between C2 and C3 in acyl-CoA is converted to a double bond.
• Compound: Delta-2-trans-enoyl-CoA with trans orientation of hydrogen atoms.
• Enzyme: Acyl-CoA dehydrogenase.
• Reaction Type: Oxidation.
• Outcome: Transfer of 2 electrons and 2 protons to FAD, forming FADH2.

Step 2: Formation of Beta-Hydroxyacyl-CoA

• Process: Addition of water molecule to double bond by enoyl-CoA hydratase.
• Result: Restoration of single bond and hydroxyl group attachment to beta-carbon.
• Reaction Type: Hydration (not oxidation).

Step 3: Formation of Beta-Ketoacyl-CoA

• Process: Hydroxyl group at beta-carbon converted to keto group.
• Enzyme: 3-hydroxyacyl-CoA dehydrogenase.
• Reaction Type: Oxidation.
• Outcome: Transfer of electrons and protons to NAD+, forming NADH and H+.

Step 4: Thiolysis

• Process: Coenzyme A transferred to beta-Carbon, cleaving the molecule.
• Enzyme: Thiolase.
• Outcome: Formation of acetyl-CoA and shortened acyl-CoA.

Energy Balance

• Per cleavage of C2 unit:
  • 1 FADH2 and 1 NADH and H+ produced.
  • Total of 4 ATP molecules (1.5 ATP from FADH2, 2.5 ATP from NADH and H+).
• Mitochondrial Beta-oxidation: Complete energy yield.
• Peroxisomal Beta-oxidation: Lower energy yield due to FADH2 regeneration in peroxisome.

Special Cases

Fatty Acids with Odd Number of Carbons

• Results in propionyl-CoA, converted to succinyl-CoA for the citric acid cycle.

Unsaturated Fatty Acids

• Challenge: Presence of cis double bonds.
• Solution: Conversion of cis to trans configuration for metabolism.

Clinical Significance

• Beta-oxidation Malfunction:
  • Rare genetic defects apparent during fasting.
  • Conditions: MCAD deficiency, VLCAD deficiency, LCHAD deficiency.
• Dietary Recommendations:
  • Rich in carbohydrates, avoid fasting.
• Testing: Part of newborn screening.

Key Points

• Beta-oxidation involves four steps: oxidation, hydration, another oxidation, and thiolysis.
• Produces reducing equivalents for ATP synthesis in mitochondria.
• Special mechanisms handle odd-numbered and unsaturated fatty acids.
• Clinical conditions relate to enzyme deficiencies impacting fatty acid breakdown.

Upcoming Topics: Acetyl-CoA metabolism in the citric acid cycle.