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[Biochemistry](https://durgical.com/en/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 +1 FADH₂ +1 ATP -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](https://durgical.com/en/biochemistry/molecules/leucine/) + α-ketoglutarate ⇌ α-Ketoisocaproate + [Glutamate](https://durgical.com/en/biochemistry/molecules/glutamate/) Hands 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)](https://durgical.com/en/biochemistry/enzymes/branched-chain-keto-acid-dehydrogenase/)** irreversible α-Ketoisocaproate + coenzyme A + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) → Isovaleryl-CoA + CO₂ + NADH In 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 →](https://durgical.com/en/conditions/maple-syrup-urine-disease/)
- **Step 3 · Isovaleryl-CoA dehydrogenase (IVD)** irreversible Isovaleryl-CoA + [FAD](https://durgical.com/en/biochemistry/molecules/fad/) → 3-Methylcrotonyl-CoA + fadh2 Creates 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](https://durgical.com/en/biochemistry/molecules/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](https://durgical.com/en/biochemistry/molecules/acetoacetate/) + [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) Splits 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

- [Branched-chain amino acid breakdown (leucine route)](https://durgical.com/en/biochemistry/pathways/branched-chain-amino-acid-breakdown/)

## Related conditions

- [Maple syrup urine disease](https://durgical.com/en/conditions/maple-syrup-urine-disease/)
- [Propionic acidaemia](https://durgical.com/en/conditions/propionic-acidaemia/)
- [Methylmalonic acidaemia](https://durgical.com/en/conditions/methylmalonic-acidaemia/)

## Related

- [Leucine](https://durgical.com/en/biochemistry/molecules/leucine/)
- [Branched-chain α-keto acid dehydrogenase (BCKDH)](https://durgical.com/en/biochemistry/enzymes/branched-chain-keto-acid-dehydrogenase/)
- [Thiamine (vitamin B1)](https://durgical.com/en/biochemistry/molecules/thiamine/)
- [Biotin (vitamin B7)](https://durgical.com/en/biochemistry/molecules/biotin/)
- [Riboflavin (vitamin B2)](https://durgical.com/en/biochemistry/molecules/riboflavin/)
- [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/)
- [Acetoacetate (acetoacetic acid)](https://durgical.com/en/biochemistry/molecules/acetoacetate/)
- [Ketogenesis (ketone body synthesis)](https://durgical.com/en/biochemistry/pathways/ketogenesis/)
- [Glucogenic and ketogenic amino acids](https://durgical.com/en/biochemistry/topics/glucogenic-and-ketogenic-amino-acids/)
- [Transamination and deamination](https://durgical.com/en/biochemistry/topics/transamination-and-deamination/)
- [Glutamate (glutamic acid)](https://durgical.com/en/biochemistry/molecules/glutamate/)
- [Propionyl-CoA to succinyl-CoA](https://durgical.com/en/biochemistry/pathways/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.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Maple syrup urine disease: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/maple-syrup-urine-disease/) (MedlinePlus, US National Library of Medicine, 2026); [Isovaleric acidemia: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/isovaleric-acidemia/) (MedlinePlus, US National Library of Medicine, 2026); [3-methylcrotonyl-CoA carboxylase deficiency: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/3-methylcrotonyl-coa-carboxylase-deficiency/) (MedlinePlus, US National Library of Medicine, 2026); [3-hydroxy-3-methylglutaryl-CoA lyase deficiency: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/3-hydroxy-3-methylglutaryl-coa-lyase-deficiency/) (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.

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/branched-chain-amino-acid-breakdown/