Gnmt, or glycine N-methyltransferase, is a key enzyme in one-carbon metabolism. It catalyzes the production of methylglycine (sarcosine) by taking a methyl group from S-adenosyl-L-methionine and methylating glycine, thus clearing methionine from the body [1,2]. This process is crucial in regulating methyl group availability in mammalian cells [5].

GNMT deficiency in knockout mouse models has high penetrance in inducing the development of steatohepatitis and hepatocellular carcinoma (HCC) [2]. Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC, indicating that normal hepatic GNMT function is necessary to maintain liver health and prevent injury and HCC [3]. In bladder cancer, high GNMT expression in invasive cancer-derived cells promotes malignant phenotypes through sarcosine production [4]. In pancreatic cancer, GNMT is markedly downregulated in cell lines and early-stage patient tissue samples, suggesting its potential as a biomarker and therapeutic target [6].

In conclusion, Gnmt plays essential roles in one-carbon metabolism and maintaining liver health. Gene knockout mouse models have revealed its significance in liver-related diseases such as steatohepatitis, HCC, as well as in other cancers like bladder and pancreatic cancer. Understanding Gnmt's function through these models provides insights into disease mechanisms and potential therapeutic strategies.

References:

1. Johnson, Adiv A, Cuellar, Trinna L. 2023. Glycine and aging: Evidence and mechanisms. In Ageing research reviews, 87, 101922. doi:10.1016/j.arr.2023.101922. https://pubmed.ncbi.nlm.nih.gov/37004845/

2. Yen, Chia-Hung, Lin, Yu-Ting, Chen, Heng-Li, Chen, Shih-Yin, Chen, Yi-Ming Arthur. 2012. The multi-functional roles of GNMT in toxicology and cancer. In Toxicology and applied pharmacology, 266, 67-75. doi:10.1016/j.taap.2012.11.003. https://pubmed.ncbi.nlm.nih.gov/23147572/

3. Lu, Shelly C, Mato, José M. . S-adenosylmethionine in liver health, injury, and cancer. In Physiological reviews, 92, 1515-42. doi:10.1152/physrev.00047.2011. https://pubmed.ncbi.nlm.nih.gov/23073625/

4. Kishi, Shingo, Mori, Shiori, Fujiwara-Tani, Rina, Nakagawa, Hidemitsu, Kuniyasu, Hiroki. 2023. ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production. In International journal of molecular sciences, 24, . doi:10.3390/ijms242216367. https://pubmed.ncbi.nlm.nih.gov/38003554/

5. Wang, Yi-Cheng, Chen, Yi-Ming, Lin, Yan-Jun, Liu, Shih-Ping, Chiang, En-Pei Isabel. 2011. GNMT expression increases hepatic folate contents and folate-dependent methionine synthase-mediated homocysteine remethylation. In Molecular medicine (Cambridge, Mass.), 17, 486-94. doi:10.2119/molmed.2010.00243. https://pubmed.ncbi.nlm.nih.gov/21210071/

6. Heinzman, Zachary, Schmidt, Connor, Sliwinski, Marek K, Goonesekere, Nalin C W. 2021. The Case for GNMT as a Biomarker and a Therapeutic Target in Pancreatic Cancer. In Pharmaceuticals (Basel, Switzerland), 14, . doi:10.3390/ph14030209. https://pubmed.ncbi.nlm.nih.gov/33802396/