Carbamoyl phosphate synthetase I

Carbamoyl phosphate synthetase I (CPS1) is a mitochondrial enzyme that plays a crucial role in the urea cycle, which is the metabolic pathway responsible for the detoxification of ammonia and the production of urea in the liver. CPS1 catalyzes the synthesis of carbamoyl phosphate from ammonia and bicarbonate in the presence of ATP. This reaction is the first and rate-limiting step of the urea cycle, making CPS1 essential for nitrogen metabolism and the prevention of hyperammonemia, a condition characterized by elevated levels of ammonia in the blood.

Function

CPS1 is located in the mitochondrial matrix, where it initiates the urea cycle by producing carbamoyl phosphate from ammonia (NH3), bicarbonate (HCO3-), and two molecules of ATP. The enzyme requires the presence of N-acetylglutamate (NAG) as an essential allosteric activator. NAG enhances the activity of CPS1, ensuring that the urea cycle functions efficiently, especially during periods of high protein intake or when the body needs to eliminate excess nitrogen.

Structure

The CPS1 enzyme is a large, multidomain protein encoded by the CPS1 gene located on chromosome 2. Its structure is complex, with several domains responsible for binding substrates and allosteric regulators. The enzyme's activity and stability are influenced by its conformational changes, which are essential for its function in the urea cycle.

Clinical Significance

Mutations in the CPS1 gene can lead to carbamoyl phosphate synthetase I deficiency (CPS1D), a rare autosomal recessive metabolic disorder. This condition results in reduced or absent activity of the CPS1 enzyme, leading to the accumulation of ammonia in the blood (hyperammonemia) shortly after birth. Symptoms of CPS1D include lethargy, poor feeding, vomiting, seizures, and potentially life-threatening complications if not treated promptly. Management of CPS1D involves dietary restrictions to limit protein intake and the administration of medications that facilitate the removal of ammonia from the body.

Genetics

The CPS1 gene provides instructions for making the enzyme carbamoyl phosphate synthetase I. Genetic variations in the CPS1 gene can affect the enzyme's function and lead to metabolic disorders such as CPS1 deficiency. Genetic testing can identify mutations in the CPS1 gene, which is crucial for diagnosing CPS1 deficiency and related conditions.

Treatment and Management

The treatment of CPS1 deficiency focuses on reducing ammonia levels in the blood through dietary protein restriction and the use of ammonia-scavenging drugs. In severe cases, dialysis may be necessary to remove excess ammonia from the blood. Liver transplantation has been successful in some cases, providing a long-term solution for patients with CPS1 deficiency.

See Also

• Urea cycle
• Hyperammonemia
• Metabolic disorder
• Liver transplantation