CPS I

Carbamoyl Phosphate Synthetase I (CPS I) is an enzyme that plays a critical role in the urea cycle, which is the metabolic pathway in mammals responsible for the disposal of ammonia. CPS I is located in the mitochondria of liver cells and is the first and rate-limiting enzyme of the urea cycle. It catalyzes the reaction of bicarbonate and ammonia with ATP to form carbamoyl phosphate. This process is essential for the detoxification of ammonia, a toxic byproduct of protein and nucleotide metabolism, into urea for excretion from the body.

Function

CPS I is unique among the enzymes of the urea cycle for its requirement of N-acetylglutamate (NAG) as a cofactor, which serves as an essential activator of the enzyme. The activity of CPS I is tightly regulated by the concentrations of its substrates and by NAG, ensuring that the urea cycle functions efficiently in response to increases in ammonia levels in the body.

Genetics

The gene encoding Carbamoyl Phosphate Synthetase I is located on human chromosome 2 (2q35). Mutations in this gene can lead to a rare but severe metabolic disorder known as Carbamoyl Phosphate Synthetase I Deficiency (CPSID), which is inherited in an autosomal recessive manner. CPSID is characterized by an inability to metabolize ammonia effectively, leading to hyperammonemia, neurological impairment, and, if untreated, can result in death in the newborn period.

Clinical Significance

CPS I deficiency is a critical condition that requires early diagnosis and management to prevent severe neurological damage or death. Treatment typically involves dietary restrictions to limit ammonia production, administration of medications that facilitate the excretion of ammonia, and in some cases, liver transplantation.

Diagnosis

Diagnosis of CPS I deficiency involves biochemical tests to measure levels of ammonia and amino acids in the blood, as well as genetic testing to identify mutations in the CPS1 gene.

Treatment

The management of CPS I deficiency focuses on reducing ammonia levels in the blood through dietary protein restriction, supplementation with arginine or citrulline to boost the urea cycle, and the use of nitrogen-scavenging drugs. In severe cases, liver transplantation may be considered.