N-Acetylglutamate synthase

N-Acetylglutamate synthase (NAGS) is an essential enzyme in the urea cycle and amino acid metabolism. It catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl-CoA, a reaction that is crucial for the proper functioning of the urea cycle. NAG acts as an essential allosteric activator for carbamoyl phosphate synthetase I (CPS1), the first enzyme in the urea cycle, thereby regulating the flow of nitrogen into the cycle for excretion as urea. This process is vital for the detoxification of ammonia in the liver.

Function

N-Acetylglutamate synthase plays a pivotal role in the urea cycle by producing N-acetylglutamate (NAG), which is necessary for the activation of carbamoyl phosphate synthetase I (CPS1). Without NAG, the urea cycle cannot function properly, leading to the accumulation of ammonia in the blood, a condition known as hyperammonemia. NAGS is primarily found in the liver and intestinal mucosa, reflecting its key roles in metabolism and detoxification.

Genetics

The gene responsible for encoding NAGS is located on the human chromosome 17q21.31. Mutations in this gene can lead to N-acetylglutamate synthase deficiency, a rare autosomal recessive disorder that disrupts the urea cycle, resulting in hyperammonemia. Early diagnosis and treatment are crucial for managing this condition.

Clinical Significance

N-Acetylglutamate synthase deficiency is characterized by an inability to synthesize N-acetylglutamate, leading to a severe impairment of the urea cycle. This condition presents early in life with symptoms of hyperammonemia, which include poor feeding, vomiting, lethargy, and in severe cases, neurological damage and death if untreated. Treatment typically involves dietary management to limit ammonia production and supplementation with N-carbamylglutamate, a synthetic analogue of NAG that can activate CPS1 and restore urea cycle function.

Diagnosis

Diagnosis of NAGS deficiency involves biochemical tests to measure blood ammonia levels and amino acid concentrations, along with genetic testing to identify mutations in the NAGS gene. Early detection and intervention are critical for preventing the severe consequences of hyperammonemia.

Treatment

Management of NAGS deficiency focuses on reducing ammonia levels in the blood through dietary restrictions and the use of medications such as N-carbamylglutamate. Liver transplantation may be considered in severe cases where conventional treatments are ineffective.

See Also

• Urea cycle
• Hyperammonemia
• Carbamoyl phosphate synthetase I
• Amino acid metabolism