Biochemistry · Enzyme
Carbamoyl phosphate synthetase I (CPS-I) !
CPS-I opens the urea cycle in liver mitochondria: it joins ammonia and CO₂ using 2 ATP to make carbamoyl phosphate.
Updated 2026-11-01
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Key facts
- 2 ATP + NH₄⁺ + HCO₃⁻ → carbamoyl phosphate + 2 ADP + Pi; the rate-limiting step of the urea cycle.
- It is mitochondrial and uses free ammonia; CPS-II is cytosolic, uses glutamine and serves pyrimidine synthesis.
- Its required allosteric activator is N-acetylglutamate.
- It is one of the most abundant proteins of the hepatocyte mitochondrial matrix.
Structure
- 5DOU shows human CPS-I with N-acetylglutamate, ADP and phosphate bound; each chain has about 1500 amino acids.
Regulation
- Without N-acetylglutamate the enzyme barely works.
- Arginine activates NAG synthase and so, indirectly, CPS-I.
- A high-protein diet and fasting hormones increase its synthesis.
Inhibitors and toxins
- Valproic acid and propionyl-CoA lower N-acetylglutamate and with it the enzyme's activity.
Clinical notes
- CPS-I deficiency (autosomal recessive) causes severe neonatal hyperammonaemia with low citrulline and normal orotic acid.
- Carglumic acid, an N-acetylglutamate analogue, activates the enzyme in NAG synthase deficiency and in some organic acidaemias.
Pathways
Related conditions
Related
Test yourself
Think of the answer, then tap the question to see it.
How do CPS-I and CPS-II differ?
CPS-I is mitochondrial, uses free ammonia and feeds the urea cycle; CPS-II is cytosolic, uses glutamine and feeds pyrimidine synthesis.
Why can propionic acidaemia raise ammonia?
Piled-up propionyl-CoA slows the making of N-acetylglutamate, the required activator of CPS-I.
How many ATP does CPS-I spend per carbamoyl phosphate?
Two: one activates bicarbonate and one phosphorylates carbamate.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: CPS1: Carbamoyl-phosphate synthase [ammonia], mitochondrial (human) (UniProt, 2026); Carbamoyl phosphate synthetase I deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); 5DOU: Crystal Structure of Human Carbamoyl phosphate synthetase I (CPS1), ligand-bound form (RCSB Protein Data Bank, 2026).
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