Carbamoyl-phosphate synthase 1 (CPS1) (CPS1)

Carbamoyl-phosphate synthase 1 (CPS1) is a mitochondrial enzyme that catalyzes the first and rate-limiting step of the urea cycle, converting ammonia and bicarbonate into carbamoyl phosphate (UniProt P31327). This reaction is critical for the detoxification of ammonia, a neurotoxic byproduct of protein catabolism, and its subsequent conversion into urea for excretion (NIH, StatPearls). CPS1 requires N-acetylglutamate (NAG) as an obligatory allosteric activator to function (PubMed PMID: 18640390). Genetic mutations in the CPS1 gene lead to Carbamoyl Phosphate Synthetase I Deficiency (CPS1D), a rare urea cycle disorder characterized by life-threatening hyperammonemia and neurological damage (GeneCards). Beyond its role in the liver, CPS1 is often overexpressed in certain cancers, such as lung and liver cancer, where it supports metabolic reprogramming and tumor growth (Frontiers in Oncology). The primary therapeutic agent interacting with this target is carglumic acid, a NAG analog used to treat hyperammonemia (FDA, DrugBank). Research is also ongoing into CPS1 inhibitors as potential anti-cancer therapies (PubMed).

Other names

Carbamoyl-phosphate synthetase 1CPSase 1CPSase ICarbamoyl-phosphate synthase [ammonia], mitochondrialGATD6

Carglumic acid acts as a structural analog of N-acetylglutamate (NAG), which is an essential allosteric activator of CPS1, thereby restoring enzyme activity in cases of NAG deficiency or partial CPS1 deficiency (FDA, DrugBank).