[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Carbamoyl phosphate synthetase I (CPS-I)

[Biochemistry](https://durgical.com/en/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

Loading the 3D model…

## 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.

**EC number**
[6.3.4.16](https://www.enzyme-database.org/query.php?ec=6.3.4.16)

**Genes**
CPS1

**Structure (PDB)**
[5DOU](https://www.rcsb.org/structure/5DOU)

## 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

- [Urea cycle](https://durgical.com/en/biochemistry/pathways/urea-cycle/)

## Related conditions

- [Hyperammonaemia](https://durgical.com/en/conditions/hyperammonaemia/)
- [Propionic acidaemia](https://durgical.com/en/conditions/propionic-acidaemia/)

## Related

- [Ammonia (ammonium)](https://durgical.com/en/biochemistry/molecules/ammonia/)
- [Ornithine transcarbamylase (OTC)](https://durgical.com/en/biochemistry/enzymes/ornithine-transcarbamylase/)
- [Glutamate (glutamic acid)](https://durgical.com/en/biochemistry/molecules/glutamate/)

## 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.

[Add to my cards (3)](https://durgical.app/estudiar/?add=/en/biochemistry/enzymes/carbamoyl-phosphate-synthetase-i/)

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

Sources: [CPS1: Carbamoyl-phosphate synthase [ammonia], mitochondrial (human)](https://www.uniprot.org/uniprotkb/P31327/entry) (UniProt, 2026); [Carbamoyl phosphate synthetase I deficiency: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/carbamoyl-phosphate-synthetase-i-deficiency/) (MedlinePlus, US National Library of Medicine, 2026); [5DOU: Crystal Structure of Human Carbamoyl phosphate synthetase I (CPS1), ligand-bound form](https://www.rcsb.org/structure/5DOU) (RCSB Protein Data Bank, 2026).

[← 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/enzymes/carbamoyl-phosphate-synthetase-i/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/carbamoyl-phosphate-synthetase-i/