N-Acetylglutamate synthase

glutamate and acetyl-CoA

carbamoyl phosphate synthase (CPS1). In mammals, NAGS is expressed primarily in the liver and small intestine, and is localized to the mitochondrial matrix.^[1]

plants, and so on) produce NAG through ornithine acetyltransferase (OAT), which is part of a ‘cyclic’ ornithine production pathway. NAGS is therefore used in a supportive role, replenishing NAG reserves as required. In some plants and bacteria, however, NAGS catalyzes the first step in a ‘linear’ arginine production pathway.^[2]

feedback regulation from arginine would act to signal NAGS that ammonia is plentiful within the cell, and needs to be removed, accelerating NAGS function. As it stands, the evolutionary journey of NAGS from essential synthetic enzyme to primary urea cycle controller is yet to be fully understood.^[9]

carbonyl group.^[11] Studies conducted using NAGS derived from Neisseria gonorrhoeae suggest that NAGS proceeds through the previously described one-step mechanism.^[12] In this proposal, the carbonyl group 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.^[13][14]

N-acetylglutamate synthase deficiency, a form of hyperammonemia.^[15] In many vertebrates, N-acetylglutamate is an essential allosteric cofactor of CPS1, the enzyme that catalyzes the first step of the urea cycle.^[16] Without NAG stimulation, CPS1 cannot convert ammonia to carbamoyl phosphate, resulting in toxic ammonia accumulation.^[17] Carbamoyl glutamate has shown promise as a possible treatment for NAGS deficiency.^[15] 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.^[14]