Precision medicine in rare disease: Mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes

- N-carbamyl-L-glutamate activates CPS1 sub-optimally compared to N-acetyl-L-glutamate even at maximal concentration.
- N-carbamyl-L-glutamate with MgATP stabilizes carbamyl phosphate synthetase 1
- N-carbamyl-L-glutamate has disparate effects on CPS1 E1034G and M792I mutations in ureagenesis.
- Treatment of patients with CPS1 deficiency with N-carbamyl-L-glutamate needs to be carefully considered and monitored.

This study documents the disparate therapeutic effect of N-carbamyl-l-glutamate (NCG) in the activation of two different disease-causing mutants of carbamyl phosphate synthetase 1 (CPS1). We investigated the effects of NCG on purified recombinant wild-type (WT) mouse CPS1 and its human corresponding E1034G (increased ureagenesis on NCG) and M792I (decreased ureagenesis on NCG) mutants. NCG activates WT CPS1 sub-optimally compared to NAG. Similar to NAG, NCG, in combination with MgATP, stabilizes the enzyme, but competes with NAG binding to the enzyme. NCG supplementation activates available E1034G mutant CPS1 molecules not bound to NAG enhancing ureagenesis. Conversely, NCG competes with NAG binding to the scarce M792I mutant enzyme further decreasing residual ureagenesis. These results correlate with the respective patient's response to NCG. Particular caution should be taken in the administration of NCG to patients with hyperammonemia before their molecular bases of their urea cycle disorders is known.