ASS1

ASS1, short for argininosuccinate synthetase 1, is a cytosolic enzyme of the urea cycle. It catalyzes the ATP-dependent condensation of citrulline and aspartate to form argininosuccinate, a reaction that also produces AMP and pyrophosphate. Argininosuccinate is then cleaved by argininosuccinate lyase to yield arginine and fumarate. By supplying arginine, ASS1 supports the continuation of the urea cycle and the disposal of excess nitrogen.

The ASS1 gene encodes the enzyme and is located on chromosome 9q34.11. The gene is expressed in liver and other tissues capable of urea cycle activity, with activity contributing to systemic nitrogen balance. The urea cycle primarily operates in hepatocytes, and ASS1 activity is a key step in converting citrulline into argininosuccinate for eventual arginine production.

Clinical significance: Deficiency of ASS1 causes citrullinemia type I, an autosomal recessive urea cycle disorder. Affected individuals typically present in the neonatal period with hyperammonemia, lethargy, poor feeding, vomiting, and seizures. Biochemical testing shows elevated plasma citrulline and reduced or absent argininosuccinate production. Management includes a protein-restricted diet, nitrogen scavengers, and arginine supplementation to support downstream cycle steps; liver or combined liver-kidney transplantation can be curative in severe cases. Newborn screening in many regions enables early detection and treatment.

Genetics and research: ASS1 mutations are diverse, including missense, nonsense, and splice-site changes. In oncology, some tumors down-regulate ASS1, creating arginine auxotrophy; this has prompted research into arginine-deprivation therapies for ASS1-deficient cancers.