of acetyl-CoA is attacked directly by the α-amino nitrogen of glutamate. This mechanism is supported by the activation of the carbonyl through hydrogen bond polarization, as well as the absence of a suitable cysteine within the active site to act as an intermediate acceptor of the acetyl group. Clinical significance Inactivity of NAGS results in N-acetylglutamate synthase deficiency, a form of hyperammonemia. In many vertebrates, N-acetylglutamate is an essential allosteric cofactor of CPS1, the enzyme that catalyzes the first step of the urea cycle. Without NAG stimulation, CPS1 cannot convert ammonia to carbamoyl phosphate, resulting in toxic ammonia accumulation. Carbamoyl glutamate has shown promise as a possible treatment for NAGS deficiency. This is suspected to be a result of the structural similarities between NAG and carbamoyl glutamate, which allows carbamoyl glutamate to act as an effective agonist for CPS1. References External links GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview Urea cycle EC 2.3.1 Mitochondrial proteins