Carbamoyl-phosphate synthase 1 (ammonia) (CPS1)

Carbamoyl-phosphate synthase 1 (CPS1) is a mitochondrial ligase and the rate-limiting enzyme of the urea cycle, primarily expressed in the liver and intestinal mucosa. It catalyzes the first committed step of the cycle, converting toxic ammonia and bicarbonate into carbamoyl phosphate using two molecules of ATP, a process that requires N-acetylglutamate (NAG) as an essential allosteric activator. Genetic deficiency of CPS1 leads to carbamoyl phosphate synthetase I deficiency (CPS1D), a rare autosomal recessive disorder characterized by life-threatening hyperammonemia, which can cause irreversible neurological damage, seizures, and coma. In oncology, CPS1 is frequently overexpressed in specific malignancies, such as LKB1-deficient non-small cell lung cancer, where it supports metabolic reprogramming by providing intermediates for pyrimidine synthesis and clearing ammonia to sustain tumor growth. Therapeutic interventions include the use of Carglumic acid, a synthetic NAG analog, to restore enzyme activity in deficiency states, while small-molecule inhibitors are being developed as potential anti-cancer agents. Furthermore, the release of CPS1 into the bloodstream serves as a sensitive clinical biomarker for acute liver injury and mitochondrial dysfunction in conditions like sepsis.

Other names

CPSICPS1Carbamoyl-phosphate synthetase ICarbamoyl-phosphate synthase (ammonia) mitochondrialCarbamoyl-phosphate synthetase 1CPS1D

Allosteric activation (Carglumic acid mimics N-acetylglutamate); Competitive inhibition (DON and H3B-120 block the active site or allosteric pockets)