N-acetylglutamate

**Synthesis and function** - Formed in hepatocyte mitochondria: glutamate + acetyl-CoA → N-acetylglutamate + CoA, catalyzed by N-acetylglutamate synthase (NAGS). - Arginine allosterically activates NAGS. High amino acid load raises glutamate and arginine, so more NAG is made and CPS I is turned on. This links urea cycle activity to protein/amino acid availability. - NAG is required for CPS I activity. CPS I converts NH3 + HCO3⁻ + 2 ATP into carbamoyl phosphate, which is the rate-limiting step of the urea cycle. - Don't confuse CPS I (mitochondrial, uses free NH4⁺, needs NAG, urea cycle) with CPS II (cytosolic, uses glutamine, no NAG, pyrimidine synthesis; inhibited by UTP, activated by PRPP).

**NAGS deficiency** - Autosomal recessive (NAGS gene mutation). The presentation resembles CPS I deficiency. - Features: hyperammonemia (neonatal lethargy, poor feeding, vomiting, seizures, cerebral edema, coma), respiratory alkalosis (ammonia stimulates the respiratory center), and low BUN. - Labs: ↑ NH3, ↑ glutamine (and alanine), ↓ citrulline, ↓ arginine, and **normal or low orotic acid**. Orotic acid is not elevated because carbamoyl phosphate is not made in the mitochondria and so cannot spill into the cytosol for pyrimidine synthesis. This distinguishes it from OTC deficiency, where orotic acid is elevated. - Mechanism of CNS toxicity: excess NH3 is detoxified by glutamine synthetase, so glutamate and then α-ketoglutarate are depleted. This impairs the TCA cycle and ATP production in the brain. Glutamine accumulation causes astrocyte swelling and cerebral edema. - Treatment: **N-carbamylglutamate (carglumic acid)**, a stable NAG analog that activates CPS I directly. This is a classic board answer. Other measures are a low-protein diet, nitrogen scavengers (sodium benzoate, sodium phenylbutyrate), arginine/citrulline supplementation, and dialysis in severe cases.

**Secondary NAG deficiency** - Organic acidemias (propionic and methylmalonic acidemia) cause secondary hyperammonemia. Propionyl-CoA inhibits NAGS and depletes acetyl-CoA. Carglumic acid can also be used here. - Valproate can cause hyperammonemia by inhibiting NAGS (via valproyl-CoA) and depleting acetyl-CoA/carnitine.

**Board pearls** - Hyperammonemia with ↓ citrulline and ↓ orotic acid → CPS I or NAGS deficiency. - Hyperammonemia with ↑ orotic acid and ↓ citrulline → OTC deficiency (X-linked recessive, the most common urea cycle disorder). - Hyperammonemia with ↑ citrulline → argininosuccinate synthetase deficiency (citrullinemia) or lyase deficiency (argininosuccinic aciduria). - Treat NAGS deficiency with carglumic acid.