N-acetylglutamate (NAG) is an essential allosteric activator of which urea cycle enzyme, and what is the clinical significance of NAGS deficiency?

• A Ornithine transcarbamylase (OTC); NAGS deficiency causes citrullinemia
• B Argininosuccinate synthetase; NAGS deficiency causes argininosuccinic aciduria
• C Arginase; NAGS deficiency causes hyperargininemia
• D Carbamoyl phosphate synthetase I (CPS I); NAGS deficiency causes hyperammonemia mimicking CPS I deficiency ✓

Explanation

N-acetylglutamate synthase (NAGS) synthesises N-acetylglutamate (NAG) from acetyl-CoA and glutamate. NAG is an obligate allosteric activator of carbamoyl phosphate synthetase I (CPS I), the first and rate-limiting enzyme of the urea cycle in mitochondria. Without NAG, CPS I cannot function, and the urea cycle stops, causing severe hyperammonemia. NAGS deficiency is therefore clinically identical to CPS I deficiency (the most severe urea cycle disorder). Treatment involves N-carbamoyl-glutamate (carglumic acid), an NAG analogue that directly activates CPS I without requiring NAGS.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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