Learn / Metabolism
Metabolic pathways
Every FMK pathway as a clickable map. Pick one pathway to hammer it — next step, enzyme, regulator, cofactor, and the facts that get tested (NADPH and who needs it, rate-limiting steps, deficiencies) — or set it to all pathways for a mixed drill. Every answer says which enzyme and which pathway.
Lipolysis, carnitine shuttle & β-oxidation · Adipose (lipolysis) → mitochondrial matrix (β-oxidation); peroxisomes for very-long-chain. Enzymes sit beside the arrows; a ★ marks the rate-limiting step. The map scrolls inside its panel.
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Lipolysis, carnitine shuttle & β-oxidation
Fasting: glucagon/epinephrine → cAMP → PKA → hormone-sensitive lipase → free fatty acids + glycerol. Long-chain acyl-CoA needs the carnitine shuttle (CPT I, rate-limiting, inhibited by malonyl-CoA). Each β-oxidation round: acyl-CoA dehydrogenase (FADH₂) → hydratase → 3-hydroxyacyl-CoA DH (NADH) → thiolase → acetyl-CoA. Palmitate: 7 rounds → 8 acetyl-CoA + 7 NADH + 7 FADH₂. Acetyl-CoA activates pyruvate carboxylase and feeds ketogenesis.
Click any metabolite on the map for its reactions. Source: FMK-05.4 / 05.6 Fatty acid metabolism I & II.
Reactions
| Step | Enzyme | Cofactors | Regulation |
|---|---|---|---|
| Triacylglycerol (adipose droplet) → Free fatty acid (albumin-bound) | Hormone-sensitive lipase (+ perilipin) | — | + Glucagon; Epinephrine (β-adrenergic → cAMP → PKA phosphorylates HSL & perilipin); Cortisol − Insulin (dephosphorylates HSL; favours re-esterification) |
| Triacylglycerol (adipose droplet) → Glycerol → liver gluconeogenesis | Hormone-sensitive lipase | — | |
| Free fatty acid (albumin-bound) → Fatty acyl-CoA (cytosol) | Fatty acyl-CoA synthetase (outer membrane) | ATP → AMP + PPi (2 ATP equivalents), CoA | |
| Fatty acyl-CoA (cytosol) → Acylcarnitine | Carnitine palmitoyltransferase I (CPT I, outer membrane) ★ CPT I deficiency (liver isoform) — fasting hypoketotic hypoglycemia, hepatomegaly, LOW acylcarnitines; muscle spared CPT I deficiency → |
Carnitine | − Malonyl-CoA |
| Acylcarnitine → Fatty acyl-CoA (matrix) | Carnitine-acylcarnitine translocase → CPT II (inner membrane) CPT II deficiency (muscle isoform, adult) — exercise/fasting/cold-induced myalgia, rhabdomyolysis, myoglobinuria, ↑CK, long-chain acylcarnitines high; infantile form has cardiomyopathy CPT II deficiency → |
Carnitine regenerated | |
| Fatty acyl-CoA (matrix) → trans-Δ²-Enoyl-CoA | Acyl-CoA dehydrogenase (VLCAD / LCAD / MCAD / SCAD by chain length) MCAD deficiency — most common FAO disorder (AR): fasting/illness-triggered hypoketotic hypoglycemia, vomiting, lethargy, hepatomegaly, sudden death; ↑C8 octanoylcarnitine on newborn screen; avoid fasting, IV dextrose MCAD deficiency →VLCAD deficiency →SCAD deficiency →Jamaican vomiting sickness (hypoglycin toxicity) → |
FAD → FADH₂ | |
| trans-Δ²-Enoyl-CoA → L-3-Hydroxyacyl-CoA | Enoyl-CoA hydratase | H₂O | |
| L-3-Hydroxyacyl-CoA → 3-Ketoacyl-CoA | 3-Hydroxyacyl-CoA dehydrogenase | NAD⁺ → NADH | − High NADH (ethanol) |
| 3-Ketoacyl-CoA → Acetyl-CoA (+ acyl-CoA −2C) | Thiolase (β-ketothiolase) | CoA | |
| Acetyl-CoA (+ acyl-CoA −2C) → Fatty acyl-CoA (matrix) | Repeat until the chain is gone | — | |
| Acetyl-CoA (+ acyl-CoA −2C) → TCA / ketogenesis | Citrate synthase / HMG-CoA synthase | — | |
| Acetyl-CoA (+ acyl-CoA −2C) → Pyruvate carboxylase activated | Allosteric activation | — |
Conditions that live on this map
CPT I deficiencyCPT II deficiencyJamaican vomiting sickness (hypoglycin toxicity)MCAD deficiencyPrimary (systemic) carnitine deficiencyRefsum diseaseReye syndromeSCAD deficiencyVLCAD deficiencyX-linked adrenoleukodystrophy (X-ALD)Zellweger syndrome
Blue pills sit on one specific arrow; grey ones are whole-pathway problems. Each opens the full condition card, which links back here with the arrow lit.
Facts worth knowing
Yield
- Products of one round of β-oxidation — 1 acetyl-CoA + 1 NADH + 1 FADH₂ and an acyl-CoA two carbons shorter
- Products of complete β-oxidation of palmitate (C16) — 8 acetyl-CoA + 7 NADH + 7 FADH₂ (7 rounds) ≈ 106 ATP net after the 2 ATP activation cost
Regulation
- Where the carnitine pool lives and where carnitine comes from — ~97% in skeletal muscle; from diet (meat) and liver/kidney synthesis from lysine + methionine
- Fatty acids that don't need the carnitine shuttle — Short- and medium-chain (≤ C10) — they diffuse in and are activated in the matrix; basis of MCT oil for CPT/ VLCAD defects
- Where very-long-chain fatty acids (> C22) are oxidised first — Peroxisomes — acyl-CoA oxidase makes H₂O₂ (not FADH₂); the shortened chain then goes to mitochondria
Enzyme deficiency
- Pattern that says 'fatty acid oxidation defect' — Hypoglycemia with inappropriately LOW/absent ketones (hypoketotic hypoglycemia) — starvation would show HIGH ketones
- Lab that separates primary carnitine deficiency from MCAD/CPT defects — Plasma free carnitine: very LOW in OCTN2 transporter deficiency; normal-to-high specific acylcarnitines when an enzyme downstream is blocked
- FAO disorder with dilated cardiomyopathy that is reversed by oral L-carnitine — Primary carnitine deficiency (OCTN2 transporter)
- Peroxisomal biogenesis disorder (PEX genes) — hypotonia, seizures, dysmorphism, fatal in infancy — Zellweger syndrome
- ABCD1 transporter defect — progressive demyelination and adrenal insufficiency in boys — X-linked adrenoleukodystrophy (VLCFA accumulate)
- Phytanoyl-CoA hydroxylase (α-oxidation) defect — retinitis pigmentosa, neuropathy, ataxia, anosmia — Refsum disease (diet-manageable)
- Mimics of an FAO defect to know — Jamaican vomiting sickness (hypoglycin from unripe ackee) and Reye syndrome (aspirin + viral illness)
- Deficiency of Carnitine palmitoyltransferase I (CPT I, outer membrane) causes… — CPT I deficiency (liver isoform) — fasting hypoketotic hypoglycemia, hepatomegaly, LOW acylcarnitines; muscle spared (Rate-limiting step of β-oxidation. Fed state: ↑malonyl-CoA → CPT I off. Fasting: ↓malonyl-CoA → fatty acids enter. Medium/short-chain fatty acids skip the shuttle.)
- Deficiency of Carnitine-acylcarnitine translocase → CPT II (inner membrane) causes… — CPT II deficiency (muscle isoform, adult) — exercise/fasting/cold-induced myalgia, rhabdomyolysis, myoglobinuria, ↑CK, long-chain acylcarnitines high; infantile form has cardiomyopathy (CPT II regenerates acyl-CoA inside the matrix.)
- Deficiency of Acyl-CoA dehydrogenase (VLCAD / LCAD / MCAD / SCAD by chain length) causes… — MCAD deficiency — most common FAO disorder (AR): fasting/illness-triggered hypoketotic hypoglycemia, vomiting, lethargy, hepatomegaly, sudden death; ↑C8 octanoylcarnitine on newborn screen; avoid fasting, IV dextrose (First oxidation. MCAD handles C6–C10; VLCAD > C14. FADH₂ goes to ETF → CoQ.)
Rate-limiting step
- Rate-limiting enzyme of lipolysis, carnitine shuttle & β-oxidation — Carnitine palmitoyltransferase I (CPT I, outer membrane) (Rate-limiting step of β-oxidation. Fed state: ↑malonyl-CoA → CPT I off. Fasting: ↓malonyl-CoA → fatty acids enter. Medium/short-chain fatty acids skip the shuttle.)