Normal enzyme function of N-acetylglutamate synthetase (NAGS) deficiency is confined to the hepatic mitochondria and mediates the reaction acetyl-coenzyme A (CoA) + glutamate → N-acetylglutamate + CoA. As a mitochondrial reaction, each of the substrates is normally omnipresent. Acetyl-CoA is a cofactor in many mitochondrial reactions, and glutamate is the transamination product of α-ketoglutarate and alanine; α-ketoglutarate is produced by the Krebs cycle.
The normal function of N-acetylglutamate (NAG), the reaction product, is to act as an activator of carbamyl phosphate synthetase (CPS), which is also a mitochondrial enzyme. See the image below.
Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
The activation process requires physical binding of NAG to the CPS enzyme, in turn, causing the inactive form of CPS to convert to an active state. Thus, CPS activity is regulated by the relationship of available NAG to inactive CPS enzyme protein.
The biochemical effect of NAGS deficiency is an inability to form adequate NAG; this results in failure to activate the enzyme responsible for the reaction NH4+ + CO2 + ATP → H2 N-CO-PO32- + ADP, which is the entry step into the urea cycle (see Carbamyl Phosphate Synthetase Deficiency).
Clinical signs and symptoms of NAGS deficiency occur when ammonia fails to fix into carbamoyl phosphate (CP) effectively, thus disabling the urea cycle. This leads to accumulation of alanine and glutamine (transamination products of pyruvate and glutamate, respectively) and, finally, of ammonia. The condition is progressive without intervention.