Fatty acid β-oxidation

Category: catabolism

Overview

Mitochondrial degradation of fatty acyl-CoA into acetyl-CoA + FADH2 + NADH. Long-chain fatty acids must first traverse the inner mitochondrial membrane via the CARNITINE SHUTTLE (CPT1 outer, CACT translocase, CPT2 inner) — CPT1 is the major regulatory step, inhibited by malonyl-CoA (the link to fatty acid synthesis: high malonyl-CoA → cytosolic FA synthesis ON, mitochondrial β-oxidation OFF). Each β-oxidation cycle: acyl-CoA → enoyl-CoA (FAD) → 3-OH-acyl-CoA → 3-ketoacyl-CoA (NAD) → shortened acyl-CoA + acetyl-CoA. Cycle repeats until the acyl chain is fully consumed. Carnitine deficiency (genetic or valproate-induced) presents as hypoketotic hypoglycemia + cardiomyopathy + Reye-like syndrome.

Organ Systems

Pathway Steps

  1. fatty-acyl-coa → enoyl-coa — via acyl-CoA dehydrogenase (FAD → FADH2). The first oxidation, by chain-length-specific acyl-CoA dehydrogenases (VLCAD/MCAD/SCAD), passes electrons via FAD → ETF → ubiquinone. MCAD deficiency is a common inborn error causing hypoketotic hypoglycemia during fasting.
  2. enoyl-coa → 3-hydroxyacyl-coa — via enoyl-CoA hydratase. Enoyl-CoA hydratase adds water across the trans double bond to give L-3-hydroxyacyl-CoA — the hydration step of each β-oxidation spiral.
  3. 3-hydroxyacyl-coa → 3-ketoacyl-coa — via 3-OH-acyl-CoA dehydrogenase (NAD → NADH). 3-hydroxyacyl-CoA dehydrogenase oxidizes the hydroxyl to a keto group, generating the cycle’s NADH (its second oxidation).
  4. 3-ketoacyl-coa → acetyl-coa — via β-ketothiolase (also produces a shortened acyl-CoA for next cycle). β-ketothiolase cleaves the bond with CoA, releasing acetyl-CoA plus a fatty-acyl-CoA shortened by two carbons that re-enters the spiral. Acetyl-CoA feeds the TCA cycle — or ketogenesis when oxaloacetate is scarce; each spiral nets 1 FADH₂ + 1 NADH + 1 acetyl-CoA.

Known Modulators

References