Fatty Acid β-Oxidation
| Rate-Limiting Enzyme: | Carnitine Acyltransferase I (CAT-1 / CPT-1) |
| Cellular Location: | Mitochondrial Matrix (Activation occurs on the outer membrane) |
| Pathway Inhibitor: | Malonyl-CoA (Prevents futile cycling during synthesis) |
| 4-Step Cycle Yield: | 1 NADH, 1 FADH2, 1 Acetyl-CoA (Per cut) |
High-Yield Core Realities:
- The Carnitine Shuttle: Long-chain fatty acids (LCFAs) cannot cross the inner mitochondrial membrane alone. They require conversion to acylcarnitine via **CPT-1**. Inherited carnitine deficiencies prevent LCFA entry, causing hypoketotic hypoglycemia, muscle weakness, and elevated serum transaminases.
- MCAD Deficiency: Autosomal recessive defect in Medium-Chain Acyl-CoA Dehydrogenase. Cannot break down 6-to 12-carbon fatty acids. Presents in infancy/early childhood during fasting with severe **hypoketotic hypoglycemia**, vomiting, lethargy, and liver dysfunction. Crucial marker: Dicarboxylic acids in urine.
- Odd-Chain Fatty Acids Exception: Unlike even-chain variants, which yield only Acetyl-CoA, odd-chain fatty acids are metabolized down to a final 3-carbon **Propionyl-CoA**. Propionyl-CoA enters gluconeogenesis via conversion to Methylmalonyl-CoA (requires Vitamin B7) and then to Succinyl-CoA (requires Vitamin B12).
- Zellweger Syndrome & Adrenoleukodystrophy (ALD): Very-long-chain fatty acids (VLCFAs, 22+ carbons) cannot undergo mitochondrial β-oxidation. They must undergo preliminary oxidation inside **peroxisomes**. Peroxisomal biogenesis failure (Zellweger) or ABCD1 transporter defects (X-linked ALD) trap VLCFAs, causing neurodegeneration and adrenal crisis.