Biochemistry · Metabolic pathway

Urea cycle !

The liver turns ammonia, which is toxic to the brain, into urea that leaves in the urine. It does so with a cycle of five enzymes.

Updated 2026-11-01

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Balance: ATP -4nh3 -1CO₂ -1

Key facts

It runs only in the liver (periportal hepatocytes): the first two steps in the mitochondrion, the other three in the cytosol.
Each urea carries two nitrogens: one from free ammonia (via CPS-I) and one from aspartate (via argininosuccinate synthetase).
One turn costs 3 ATP, worth 4 high-energy phosphate bonds: 2 at CPS-I and 2 at argininosuccinate synthetase (ATP → AMP).
CPS-I is the rate-limiting step and works only with its allosteric activator, N-acetylglutamate.
The fumarate released by argininosuccinate lyase links to the Krebs cycle (the «Krebs bicycle»).

Also called: Ornithine cycle, Krebs–Henseleit cycle

Regulation

N-acetylglutamate activates CPS-I; NAG synthase makes it from glutamate and acetyl-CoA, and arginine stimulates that synthase.
High-protein diets and prolonged fasting (glucagon, cortisol) raise the amount of all five enzymes.
Flux also follows substrate supply: more ammonia and more ornithine speed the cycle up.

The steps, one by one

Entry · Carbamoyl phosphate synthetase I (CPS-I) irreversible Ammonia + CO₂ + ATP → Carbamoyl phosphate + ADP + phosphate (Pi)In the mitochondrion it joins ammonia and bicarbonate (CO₂), spending 2 ATP, to make carbamoyl phosphate; this is the cycle's entry.If it fails: CPS-I deficiency (autosomal recessive): severe neonatal hyperammonaemia with normal orotic acid. Hyperammonaemia →
Step 1 · Ornithine transcarbamylase (OTC) irreversible Ornithine + Carbamoyl phosphate → Citrulline + phosphate (Pi)Still in the mitochondrion, it moves the carbamoyl group onto ornithine to make citrulline, which leaves for the cytosol.If it fails: OTC deficiency (X-linked): hyperammonaemia with high urinary orotic acid; the most common urea cycle disorder. Ornithine transcarbamylase (OTC) deficiency →
Step 2 · Argininosuccinate synthetase (ASS) irreversible Citrulline + Aspartate + ATP → Argininosuccinate + amp + pyrophosphateIn the cytosol it joins citrulline to aspartate, which brings the second nitrogen of urea.If it fails: Citrullinaemia type I (ASS1 gene): hyperammonaemia with very high plasma citrulline. Hyperammonaemia →
Step 3 · Argininosuccinate lyase (ASL) Argininosuccinate ⇌ Arginine + fumarateSplits argininosuccinate into arginine and fumarate; the fumarate goes back to the Krebs cycle.If it fails: Argininosuccinic aciduria: hyperammonaemia, brittle hair (trichorrhexis nodosa) and liver damage. Hyperammonaemia →
Step 4 · Arginase 1 irreversible Arginine + H₂O → Ornithine + UreaHydrolyses arginine: releases urea and regenerates ornithine, which returns to the mitochondrion for another turn.If it fails: Arginase deficiency: progressive spastic diplegia; ammonia rises less than in the other defects. Hyperammonaemia →

Clinical notes

A defect in any of its enzymes causes hyperammonaemia; the most common is X-linked OTC deficiency.
In cirrhosis, the damaged liver and portosystemic shunts let ammonia reach the brain: hepatic encephalopathy.
In OTC deficiency urinary orotic acid rises (spare carbamoyl phosphate enters the pyrimidine pathway); in CPS-I deficiency it does not.
Blood urea (BUN) falls in severe liver failure and rises in kidney failure or after an upper GI bleed.

Pathways

Urea cycle

Test yourself

Think of the answer, then tap the question to see it.

Where do the two nitrogens of urea come from?

One from free ammonia, which enters through CPS-I, and one from aspartate, which enters through argininosuccinate synthetase.

Which molecule is the required activator of CPS-I?

N-acetylglutamate, made by NAG synthase from glutamate and acetyl-CoA; arginine stimulates its synthesis.

Which finding separates OTC deficiency from CPS-I deficiency?

Urinary orotic acid is high in OTC deficiency: the piled-up carbamoyl phosphate enters the pyrimidine pathway. In CPS-I deficiency none is made.

How much energy does one turn of the cycle cost?

3 ATP, worth 4 high-energy bonds, because argininosuccinate synthetase turns ATP into AMP and pyrophosphate.

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

Sources: Urea cycle (Reactome, 2026); Hereditary urea cycle abnormality: MedlinePlus Medical Encyclopedia (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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