NAGS, short for N-acetylglutamate synthase, is a mitochondrial enzyme. It catalyzes the formation of N-acetylglutamate (NAG), which is an essential allosteric activator of carbamylphosphate synthetase I (CPSI) in the urea cycle [2]. In microorganisms and plants, it functions in the arginine biosynthetic pathway, while in mammals, its major role is in the urea cycle to detoxify ammonia [6].

Median expression of NAGS mRNA was higher in glioblastoma multiforme (GBM), glioma, and stomach adenocarcinoma samples compared to matched normal tissue. High NAGS expression was associated with an unfavorable outcome in patients with glioblastoma and GBM, while low NAGS expression was associated with an unfavorable outcome in patients with lung adenocarcinoma [1]. Inherited NAGS deficiency results in hyperammonemia, presumably due to loss of CPSI activity. Mutations in NAGS have been identified in families with neonatal and late-onset NAGS deficiency [2]. NAGS deficiency is an autosomal recessive urea cycle disorder, presenting with recurrent encephalopathy in adults and life-threatening hyperammonemia in neonates [3,5].

In conclusion, NAGS is crucial for the proper functioning of the urea cycle by activating CPSI. Studies on NAGS-related conditions such as deficiency and its role in tumors have provided insights into its importance in preventing hyperammonemia and in tumorigenesis. Understanding NAGS through research helps in better management of urea cycle disorders and potentially, in developing strategies for treating certain tumors [1,2,3,4,5].

References:

1. Owusu-Ansah, Melissa, Guptan, Nikita, Alindogan, Dylon, Morizono, Michio, Caldovic, Ljubica. 2023. NAGS, CPS1, and SLC25A13 (Citrin) at the Crossroads of Arginine and Pyrimidines Metabolism in Tumor Cells. In International journal of molecular sciences, 24, . doi:10.3390/ijms24076754. https://pubmed.ncbi.nlm.nih.gov/37047726/

2. Morizono, Hiroki, Caldovic, Ljubica, Shi, Dashuang, Tuchman, Mendel. . Mammalian N-acetylglutamate synthase. In Molecular genetics and metabolism, 81 Suppl 1, S4-11. doi:. https://pubmed.ncbi.nlm.nih.gov/15050968/

3. Cartagena, A, Prasad, A N, Rupar, C A, Ah Mew, N, Prasad, C. . Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. In The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 40, 3-9. doi:. https://pubmed.ncbi.nlm.nih.gov/23250120/

4. Kenneson, Aileen, Singh, Rani H. 2020. Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature. In Orphanet journal of rare diseases, 15, 279. doi:10.1186/s13023-020-01560-z. https://pubmed.ncbi.nlm.nih.gov/33036647/

5. Peoc'h, Katell, Damaj, Léna, Pelletier, Romain, Odent, Sylvie, Moreau, Caroline. 2020. Early care of N-acetyl glutamate synthase (NAGS) deficiency in three infants from an inbred family. In Molecular genetics and metabolism reports, 22, 100558. doi:10.1016/j.ymgmr.2019.100558. https://pubmed.ncbi.nlm.nih.gov/32021803/

6. Shi, Dashuang, Allewell, Norma M, Tuchman, Mendel. 2015. The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms. In International journal of molecular sciences, 16, 13004-22. doi:10.3390/ijms160613004. https://pubmed.ncbi.nlm.nih.gov/26068232/