CPS1

CPS1 (carbamoyl-phosphate synthase [ammonia], mitochondrial) is a ~1500-residue multidomain enzyme of the mitochondrial matrix that catalyzes the first and rate-limiting committed step of the urea cycle in ureotelic animals: the ATP-dependent condensation of ammonia and bicarbonate into carbamoyl phosphate (NH4+ + HCO3- + 2 ATP -> carbamoyl phosphate + 2 ADP + phosphate + 2 H+; EC 6.3.4.16). It is highly expressed in liver and small intestine, where it initiates hepatic detoxification of ammonia derived from amino acid catabolism. Unlike the cytosolic glutamine-dependent CPS II (part of CAD) that feeds pyrimidine biosynthesis, CPS1 uses free ammonia rather than glutamine; its ancestral glutamine amidotransferase domain is catalytically defective (the catalytic cysteine is replaced by Ser294). CPS1 is an allosteric enzyme with an absolute requirement for the activator N-acetyl-L-glutamate (NAG), which binds the C-terminal MGS-like domain and, together with nucleotide binding, drives long-range conformational changes that build the intramolecular tunnel through which the labile carbamate intermediate migrates between the two ATP-grasp phosphorylation sites; in the absence of NAG the enzyme retains <=2% of its maximal activity. Catalysis also requires the ionic activators potassium and magnesium. The enzyme behaves in solution as a monomer-dimer equilibrium in which the monomer predominates. Loss-of-function variants cause the autosomal recessive urea-cycle disorder carbamoyl phosphate synthetase 1 deficiency (CPS1D), which presents most severely as neonatal hyperammonemia with high mortality and neurological sequelae.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

• metabolic_intoxication_decompensation via Carbamoyl Phosphate Synthetase I Deficiency