beta oxidation

Fatty acids are first activated in the cytosol to fatty acyl-CoA (via fatty acyl-CoA synthetase), then transported into the mitochondrial matrix using the carnitine shuttle (carnitine acyltransferase I and II), which is the rate-limiting step regulated by malonyl-CoA (an inhibitor of CPT-I, linking fatty acid synthesis and oxidation). Once inside the mitochondria, beta oxidation proceeds through four repeating enzymatic steps: (1) oxidation by acyl-CoA dehydrogenase (producing FADH2), (2) hydration, (3) oxidation by hydroxyacyl-CoA dehydrogenase (producing NADH), and (4) thiolytic cleavage releasing acetyl-CoA and a shortened fatty acyl-CoA. This cycle repeats until the fatty acid is fully degraded into acetyl-CoA units, which enter the TCA cycle for further ATP generation, or in the liver, contribute to ketone body synthesis during prolonged fasting. Odd-chain fatty acids yield propionyl-CoA in the final round, which is converted to succinyl-CoA (via methylmalonyl-CoA, requiring vitamin B12) and enters the TCA cycle—clinically relevant in disorders of B12 or biotin metabolism. Clinically important is Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD deficiency), an autosomal recessive disorder causing hypoketotic hypoglycemia, vomiting, and lethargy during fasting due to inability to break down medium-chain fatty acids; it's part of newborn screening panels. Systemic carnitine deficiency and CPT-I/II deficiencies also impair beta oxidation, causing muscle weakness, hypoketotic hypoglycemia, and cardiomyopathy. Genetics of fatty acid oxidation defects are tested extensively on USMLE Step 1 due to their classic presentations and biochemical connections to the TCA cycle, ketogenesis, and glycolysis regulation.