Cps1, also known as carbamoyl phosphate synthetase 1, is the first and rate-limiting enzyme of the urea cycle. It is responsible for converting toxic ammonia into non-toxic urea in mammals by producing carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, thus initiating nitrogen disposal [2,3]. The urea cycle is crucial for siphoning catabolic waste nitrogen for excretion, and disruptions in Cps1 function can lead to elevated ammonia and neurological injury [2].

In KRAS/LKB1-mutant (KL) non-small-cell lung cancer (NSCLC) cells, Cps1 is expressed, and its transcription is suppressed by LKB1 through AMPK. Silencing Cps1 in KL cells induces cell death and reduces tumour growth. The cell death is due to pyrimidine depletion rather than ammonia toxicity, as Cps1 enables an unconventional nitrogen flow pathway from ammonia into pyrimidines, maintaining pyrimidine pools and DNA synthesis [1]. In APAP-induced drug-induced liver failure, GSDME-dependent non-canonical pyroptosis promotes Cps1 deISGylation and degradation, causing ammonia clearance dysfunction, and GSDME deletion can prevent these effects [4].

In conclusion, Cps1 plays a vital role in nitrogen metabolism, especially in the urea cycle for ammonia detoxification. Its study in disease models, such as in KL-mutant NSCLC cells and APAP-induced liver failure, reveals its significance in cancer metabolism and liver function. Understanding Cps1's function through gene-knockout models provides insights into the pathogenesis of related diseases and potential therapeutic targets.

References:

1. Kim, Jiyeon, Hu, Zeping, Cai, Ling, Minna, John D, DeBerardinis, Ralph J. 2017. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. In Nature, 546, 168-172. doi:10.1038/nature22359. https://pubmed.ncbi.nlm.nih.gov/28538732/

2. Nitzahn, Matthew, Lipshutz, Gerald S. 2020. CPS1: Looking at an ancient enzyme in a modern light. In Molecular genetics and metabolism, 131, 289-298. doi:10.1016/j.ymgme.2020.10.003. https://pubmed.ncbi.nlm.nih.gov/33317798/

3. Zhang, Lan, Zou, Yuling, Lu, Yingying, Li, Zhijia, Gao, Feng. 2022. Unraveling the therapeutic potential of carbamoyl phosphate synthetase 1 (CPS1) in human diseases. In Bioorganic chemistry, 130, 106253. doi:10.1016/j.bioorg.2022.106253. https://pubmed.ncbi.nlm.nih.gov/36356370/

4. Ouyang, Shen-Xi, Zhu, Jia-Hui, Cao, Qi, Li, Dong-Jie, Wang, Pei. 2024. Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2305715. doi:10.1002/advs.202305715. https://pubmed.ncbi.nlm.nih.gov/38417117/