[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Urea cycle [Biochemistry](https://durgical.com/en/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 ## Interactive map **Balance:** ATP -4 nh3 -1 CO₂ -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)](https://durgical.com/en/biochemistry/enzymes/carbamoyl-phosphate-synthetase-i/)** irreversible [Ammonia](https://durgical.com/en/biochemistry/molecules/ammonia/) + CO₂ + [ATP](https://durgical.com/en/biochemistry/molecules/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 →](https://durgical.com/en/conditions/hyperammonaemia/) - **Step 1 · [Ornithine transcarbamylase (OTC)](https://durgical.com/en/biochemistry/enzymes/ornithine-transcarbamylase/)** 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 →](https://durgical.com/en/conditions/ornithine-transcarbamylase-deficiency/) - **Step 2 · [Argininosuccinate synthetase (ASS)](https://durgical.com/en/biochemistry/enzymes/argininosuccinate-synthetase/)** irreversible Citrulline + Aspartate + [ATP](https://durgical.com/en/biochemistry/molecules/atp/) → Argininosuccinate + amp + pyrophosphate In 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 →](https://durgical.com/en/conditions/hyperammonaemia/) - **Step 3 · [Argininosuccinate lyase (ASL)](https://durgical.com/en/biochemistry/enzymes/argininosuccinate-lyase/)** Argininosuccinate ⇌ Arginine + fumarate Splits 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 →](https://durgical.com/en/conditions/hyperammonaemia/) - **Step 4 · [Arginase 1](https://durgical.com/en/biochemistry/enzymes/arginase-1/)** irreversible Arginine + H₂O → Ornithine + [Urea](https://durgical.com/en/biochemistry/molecules/urea/) Hydrolyses 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 →](https://durgical.com/en/conditions/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](https://durgical.com/en/biochemistry/pathways/urea-cycle/) ## Related conditions - [Ornithine transcarbamylase (OTC) deficiency](https://durgical.com/en/conditions/ornithine-transcarbamylase-deficiency/) - [Hyperammonaemia](https://durgical.com/en/conditions/hyperammonaemia/) - [Cirrhosis](https://durgical.com/en/conditions/cirrhosis/) - [Portal hypertension](https://durgical.com/en/conditions/portal-hypertension/) ## Related - [Ammonia (ammonium)](https://durgical.com/en/biochemistry/molecules/ammonia/) - [Urea](https://durgical.com/en/biochemistry/molecules/urea/) - [Glutamate (glutamic acid)](https://durgical.com/en/biochemistry/molecules/glutamate/) - [Glutamine](https://durgical.com/en/biochemistry/molecules/glutamine/) - [Carbamoyl phosphate synthetase I (CPS-I)](https://durgical.com/en/biochemistry/enzymes/carbamoyl-phosphate-synthetase-i/) - [Ornithine transcarbamylase (OTC)](https://durgical.com/en/biochemistry/enzymes/ornithine-transcarbamylase/) - [Argininosuccinate synthetase (ASS)](https://durgical.com/en/biochemistry/enzymes/argininosuccinate-synthetase/) - [Argininosuccinate lyase (ASL)](https://durgical.com/en/biochemistry/enzymes/argininosuccinate-lyase/) - [Arginase 1](https://durgical.com/en/biochemistry/enzymes/arginase-1/) - [Glutamate dehydrogenase (GDH)](https://durgical.com/en/biochemistry/enzymes/glutamate-dehydrogenase/) - [Aspartate aminotransferase (AST, GOT)](https://durgical.com/en/biochemistry/enzymes/aspartate-aminotransferase/) - [Transamination and deamination](https://durgical.com/en/biochemistry/topics/transamination-and-deamination/) - [Krebs cycle (citric acid cycle)](https://durgical.com/en/biochemistry/pathways/krebs-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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/urea-cycle/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [Urea cycle](https://reactome.org/PathwayBrowser/#/R-HSA-70635) (Reactome, 2026); [Hereditary urea cycle abnormality: MedlinePlus Medical Encyclopedia](https://medlineplus.gov/ency/article/000372.htm) (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). [← All of biochemistry](https://durgical.com/en/biochemistry/) ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/biochemistry/pathways/urea-cycle/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/urea-cycle/