Shi Dashuang, Zhao Gengxiang, Ah Mew Nicholas, Tuchman Mendel
Center for Genetic Medicine Research, Department of Integrative Systems Biology, Children's Research Institute, Children's National Health System, The George Washington University, Washington, DC 20010, USA.
Center for Genetic Medicine Research, Department of Integrative Systems Biology, Children's Research Institute, Children's National Health System, The George Washington University, Washington, DC 20010, USA.
Mol Genet Metab. 2017 Mar;120(3):198-206. doi: 10.1016/j.ymgme.2016.12.002. Epub 2016 Dec 8.
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.
本研究记录了N-氨甲酰-L-谷氨酸（NCG）对氨甲酰磷酸合成酶1（CPS1）两种不同致病突变体激活的不同治疗效果。我们研究了NCG对纯化的重组野生型（WT）小鼠CPS1及其人类对应物E1034G（NCG作用下尿素生成增加）和M792I（NCG作用下尿素生成减少）突变体的影响。与N-乙酰谷氨酸（NAG）相比，NCG对WT CPS1的激活效果欠佳。与NAG类似，NCG与MgATP联合使用时可使酶稳定，但会与NAG竞争与酶的结合。补充NCG可激活未与NAG结合的可用E1034G突变体CPS1分子，从而增强尿素生成。相反，NCG与NAG竞争与稀少的M792I突变酶的结合，进一步降低残余尿素生成。这些结果与相应患者对NCG的反应相关。在已知尿素循环障碍分子基础之前，对高氨血症患者使用NCG时应格外谨慎。
