描述
Carbamoyl phosphate synthetase (CPS) deficiency (Carbamoyl phosphate synthetase I deficiency) is a urea cycle defect that results from a deficiency in an enzyme that mediates the normal path for incorporation of ammonia. Carbamoyl phosphate is derived from catabolism of amino acids into a 1-carbon compound, in which the carbon atom is derived from bicarbonate. The process is exclusively mitochondrial and requires the expenditure of two ATP molecules. Two hepatocellular enzymes exist: CPS I and CPS II. CPS I is exclusively intramitochondrial, and its deficiency is responsible for the disease. CPS I is the most plentiful single protein in hepatic mitochondria, accounting for about 20% of the matrix protein. CPS II is exclusively cytosolic and is an important enzyme in de novo synthesis of pyrimidine nucleotides. The regulation of CPS I activity depends on the levels of N -acetylglutamate. In patients with homozygous CPS I deficiency, the ability to fix waste nitrogen is completely absent, resulting in increasing levels of free ammonia with the attendant effects on the CNS. A recent molecular and functional examination of the mutational effects showed that, although some mutations affect both substrate affinity and efficiency of the reaction, others affect one more than the other. Some mutations are associated with enhanced RNA instability, which leads to diminished protein synthesis. The hepatic urea cycle is the major route for waste nitrogen disposal. Waste nitrogen is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and may result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate, the enzyme activator of CPS I, which initiates incorporation of ammonia into the cycle.