CPS I

Carbamoyl phosphate synthetase I (CPS1) is a mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of the urea cycle, converting ammonia and bicarbonate into carbamoyl phosphate and thereby initiating hepatic nitrogen detoxification through urea synthesis^[1][2]. CPS1 directly incorporates ammonia into urea cycle intermediates and serves as a central regulator of ammonia clearance in ureotelic organisms^[1]. Mechanistically, CPS1 activity is essential for maintaining nitrogen homeostasis, and disruption of CPS1 function impairs urea cycle flux, resulting in hyperammonemia and neurological injury associated with urea cycle disorders^[1][3][4]. In disease settings, inherited CPS1 deficiency is an autosomal recessive metabolic disorder characterized by severe hyperammonemia, encephalopathy, and potentially life-threatening clinical manifestations, making CPS1 an important experimental model for studying ammonia detoxification and urea cycle regulation^[3][4]. Compared with the related isoform CPS2, which functions in the cytosol and participates in pyrimidine biosynthesis, CPS1 is localized to mitochondria and is dedicated to the urea cycle, highlighting distinct biological roles despite catalyzing carbamoyl phosphate synthesis^[5]. Structural and biochemical studies further demonstrate that CPS1 is activated by N-acetyl-L-glutamate (NAG), an essential allosteric activator that functions as an on-off regulatory signal for ureagenesis^[1]. For experimental applications, NAG-responsive regulation and CPS1 deficiency models provide valuable systems for investigating urea cycle control, hyperammonemia pathogenesis, and therapeutic strategies targeting nitrogen metabolism^[1][3].