Biochemistry · Metabolic pathway
Branched-chain amino acid breakdown (leucine route) !
Muscle and liver break down leucine, isoleucine and valine. The map follows leucine, which ends as acetyl-CoA and acetoacetate (ketogenic).
Updated 2026-11-01
Interactive map
Balance: NADH +1FADH₂ +1ATP -1
Key facts
- The first two steps are shared by the three BCAAs: transamination (BCAT, mostly in muscle) and oxidative decarboxylation by BCKDH.
- BCKDH needs the same five cofactors as PDH: thiamine pyrophosphate, lipoate, CoA, FAD and NAD⁺.
- Leucine is purely ketogenic (acetyl-CoA + acetoacetate); valine gives succinyl-CoA (glucogenic) and isoleucine gives both.
- 3-Methylcrotonyl-CoA carboxylase needs biotin; multiple carboxylase deficiency hits it together with PCC, pyruvate carboxylase and ACC.
- BCKDH deficiency causes maple syrup urine disease; isovaleryl-CoA dehydrogenase deficiency causes isovaleric acidaemia, with a sweaty-feet smell.
- Also called
- BCAA catabolism
Regulation
- BCKDH is switched off by phosphorylation (BCKDH kinase) and on by a phosphatase (PPM1K); its own ketoacid substrates inhibit the kinase.
- Fasting, exercise and glucocorticoids increase BCAA oxidation in muscle.
- Muscle has much BCAT and little BCKDH activity, so ketoacids travel to the liver to be oxidised.
The steps, one by one
- Step 1 · Branched-chain aminotransferase (BCAT2, mitochondrial) Leucine + α-ketoglutarate ⇌ α-Ketoisocaproate + GlutamateHands the amino group of leucine to α-ketoglutarate, giving glutamate and the branched-chain ketoacid α-ketoisocaproate.If it fails: BCAT2 deficiency is very rare: BCAAs rise but, unlike MSUD, their ketoacids do not.
- Step 2 · Branched-chain α-ketoacid dehydrogenase complex (BCKDH) irreversible α-Ketoisocaproate + coenzyme A + NAD⁺ → Isovaleryl-CoA + CO₂ + NADHIn the mitochondrion it removes CO₂ from the ketoacid and joins the rest to CoA, as PDH does with pyruvate; the same complex works on all three BCAAs.If it fails: Its deficiency causes maple syrup urine disease: leucine, isoleucine, valine and their ketoacids build up, and the urine smells of burnt sugar. Maple syrup urine disease →
- Step 3 · Isovaleryl-CoA dehydrogenase (IVD) irreversible Isovaleryl-CoA + FAD → 3-Methylcrotonyl-CoA + fadh2Creates a double bond in isovaleryl-CoA and passes the electrons through FAD to the electron-transferring flavoprotein (ETF).If it fails: Isovaleric acidaemia: isovaleric acid builds up, with acidosis, vomiting and a sweaty-feet smell; glycine and carnitine help to remove it.
- Step 4 · 3-Methylcrotonyl-CoA carboxylase (MCC) irreversible 3-Methylcrotonyl-CoA + CO₂ + ATP → 3-Methylglutaconyl-CoA + ADP + phosphate (Pi)Adds CO₂ (as bicarbonate) using biotin and ATP, making 3-methylglutaconyl-CoA.If it fails: 3-MCC deficiency is often found by newborn screening; many children never have symptoms, others have episodes of hypoglycaemia and acidosis.
- Step 5 · 3-Methylglutaconyl-CoA hydratase (AUH) 3-Methylglutaconyl-CoA + H₂O ⇌ HMG-CoA (3-hydroxy-3-methylglutaryl-CoA)Adds water across the double bond to give HMG-CoA, the same intermediate used in ketogenesis.If it fails: AUH deficiency causes 3-methylglutaconic aciduria type I, a rare disorder with variable neurological signs.
- Step 6 · HMG-CoA lyase (HMGCL) irreversible HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) → Acetoacetate + Acetyl-CoASplits HMG-CoA into acetoacetate and acetyl-CoA, the end products that make leucine purely ketogenic.If it fails: HMG-CoA lyase deficiency blocks both leucine breakdown and ketone body synthesis: hypoketotic hypoglycaemia and acidosis during fasting.
Clinical notes
- Maple syrup urine disease: leucine and its ketoacid build up and cause encephalopathy and brain oedema in newborns; leucine is the most neurotoxic.
- Isovaleric acidaemia: metabolic acidosis, vomiting and a smell of sweaty feet in the newborn.
- Some patients with MSUD respond to thiamine; treatment relies on a diet low in BCAAs.
- Biotin or biotinidase deficiency affects 3-methylcrotonyl-CoA carboxylase together with the other carboxylases.
Pathways
Related conditions
Related
- Leucine
- Branched-chain α-keto acid dehydrogenase (BCKDH)
- Thiamine (vitamin B1)
- Biotin (vitamin B7)
- Riboflavin (vitamin B2)
- Acetyl-CoA
- Acetoacetate (acetoacetic acid)
- Ketogenesis (ketone body synthesis)
- Glucogenic and ketogenic amino acids
- Transamination and deamination
- Glutamate (glutamic acid)
- Propionyl-CoA to succinyl-CoA
Test yourself
Think of the answer, then tap the question to see it.
Which five cofactors does BCKDH need?
Thiamine pyrophosphate, lipoic acid, CoA, FAD and NAD⁺, the same as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase.
Why is leucine called purely ketogenic?
Its carbon skeleton ends as acetyl-CoA and acetoacetate, which cannot give net glucose.
Which amino acid is the most neurotoxic in maple syrup urine disease?
Leucine, with its ketoacid α-ketoisocaproate; its plasma level guides treatment.
Which vitamin does 3-methylcrotonyl-CoA carboxylase need?
Biotin (B7), like the other carboxylases: propionyl-CoA, pyruvate and acetyl-CoA carboxylase.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Maple syrup urine disease: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Isovaleric acidemia: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); 3-methylcrotonyl-CoA carboxylase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); 3-hydroxy-3-methylglutaryl-CoA lyase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.