carbamoyl phosphate synthetase I

CPS1 catalyzes: NH3 + CO2 + 2ATP → carbamoyl phosphate + 2ADP + Pi, the first committed step of the urea cycle, occurring in the mitochondria of hepatocytes (and intestinal mucosa). This is distinct from carbamoyl phosphate synthetase II (CPS II), which is cytosolic and functions in pyrimidine synthesis using glutamine instead of ammonia (not activated by NAG).

CPS I requires N-acetylglutamate (NAG), synthesized from acetyl-CoA and glutamate by N-acetylglutamate synthase (NAGS), as an essential allosteric activator—linking urea cycle activity to amino acid catabolism and energy status.

CPS I deficiency is an autosomal recessive urea cycle disorder presenting in neonates with hyperammonemia, lethargy, poor feeding, vomiting, tachypnea (respiratory alkalosis from stimulation of respiratory center by ammonia), and potentially progressing to seizures, coma, and cerebral edema if untreated. Unlike ornithine transcarbamylase (OTC) deficiency, CPS I deficiency does NOT cause elevated orotic acid or orotic aciduria because carbamoyl phosphate is never formed to enter the pyrimidine synthesis pathway—this is a key distinguishing lab feature on boards. Both CPS I and OTC deficiencies show low citrulline levels, but OTC deficiency (X-linked) shows increased orotic acid and orotate in urine, while CPS I deficiency does not, helping differentiate the two proximal urea cycle defects.

Treatment involves dietary protein restriction, arginine/citrulline supplementation, and nitrogen-scavenging drugs (sodium benzoate, sodium phenylacetate) to provide alternative routes for nitrogen excretion, along with hemodialysis in acute crises.

Clinical relevance: Urea cycle disorders are classic USMLE topics testing understanding of ammonia metabolism, distinguishing enzyme deficiencies via metabolite patterns (orotic acid, citrulline, argininosuccinate), and recognizing hyperammonemia's neurologic effects.