Urea cycle and nitric oxide synthesis pathway (UC/NO pathway)

The Urea cycle and nitric oxide (NO) synthesis pathway is a fundamental metabolic system primarily located in the liver and vascular endothelium that manages nitrogen homeostasis and signaling. The urea cycle consists of five core enzymes—carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase 1 (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1)—which collectively convert toxic ammonia into water-soluble urea for renal excretion (StatPearls, 2023). This pathway is intrinsically linked to NO synthesis via the arginine-citrulline cycle, where ASS1 and ASL recycle citrulline back into L-arginine, the mandatory substrate for nitric oxide synthases (NOS) (Circulation, 2000). Genetic deficiencies in these enzymes lead to urea cycle disorders (UCDs) characterized by life-threatening hyperammonemia, while dysregulation of NO production is implicated in hypertension and endothelial dysfunction (NIH GARD, 2021). Pharmacological modulation involves nitrogen-scavenging agents like sodium phenylbutyrate to bypass the cycle, substrate supplementation with L-arginine or L-citrulline to boost NO levels, and emerging enzyme replacement therapies (Nature Reviews Cancer, 2018). Furthermore, many tumors exhibit arginine auxotrophy due to ASS1 silencing, making this pathway a target for arginine-depleting metabolic therapies (PubMed, 2021).

Other names

Ornithine cycleKrebs-Henseleit cycleArginine-citrulline cycleUrea cycle

Nitrogen scavenging, enzyme replacement, allosteric activation, and substrate supplementation to restore nitrogen balance or enhance nitric oxide production.