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N-Acetylglutamate synthetase (NAGS) deficiency is a genetic disorder of ammonia detoxication. These disorders result in acute and chronic hyperammonemia, becoming evident in early infancy. They are associated with a high mortality and morbidity.

In April 1968 two female siblings, 5 years and 2 months of age respectively, came under our observation. They were the offsprings of probably consanguinous parents. The elder sibling had a history of motor and mental retardation, seizures and spasticity predominantly in the lower extremities. The younger sibling presented us with major convulsive attacks, and showed a progressive loss of motor and mental skills together with increasingly more severe spasticity of both legs, during her first year of life In addition, she had intermittant episodes of vomiting, poor appetite and lethargy, features never present in the elder girl probably because of a self-selected low protein intake. In 1971 another female sibling was born who developed the same symptoms.

Orotoc acid (OA) an intermediary metabolite of the pyrimidine synthesis pathway is formed from carbamylphosphate (CP) and aspartate (Fig. 1). In the liver these precursors are synthetised mainly in the mitochondrium1,2,3 . Natale and Tremblay4 showed that CP formed by carbamylphosphate synthetase (CPS I) in the mitochondria crosses the mitochondrial membrane into the cytosol where the condensation with aspartate occurs. In addition especially in extrahepatic, fetal or regenerating tissues a cytosolic glutamine dependant carbamylphosphate synthetase (CPS II) exists5,6. Tremblay et al. showed that the synthesis of CP in the mitochondria accounts for a major part of the CP utilized for pyrimidine synthesis by rat liver slices.

NAGS plays an important role in the short term regulation of urea synthesis. This enzyme has extensively been studied by Shigesada and Tatibana in rodents 1 ,2,3. We have purified human NAGS in order to find out what substrate concentrations should be used in an assay for human liver. The kinetic results including product inhibition studies are compatible with a rapid equilibrium random bibi mechanism. In the absence of arginine the Km are for Acetyl CoA 4.4 mmol/1, for glutamate 8.2 mmol/1. The Ki of N-acetylglutamate is at 0.5 mmol/1. Arginine approximately triples the activity (half maximum activation at about 30 µmol/1), and appears to lower the Km of acetyl CoA, but not of glutamate4.