SHMT2, or serine hydroxymethyltransferase 2, is a key enzyme in one-carbon metabolism. It converts serine into glycine and a tetrahydrofolate-bound one-carbon unit, which is crucial for thymidine and purine synthesis [2]. This process is integral to nucleotide and amino acid metabolism, and SHMT2 also participates in inflammatory cytokine signaling by interacting with the BRCC36 isopeptidase complex (BRISC) [3]. Genetic models, such as KO/CKO mouse models, can help to clarify its role in biological processes and diseases.

In a hepatocyte-specific SHMT2 knockout mouse model, the absence of SHMT2 increased serine and glycine levels in circulation, decreased liver methylation potential, and increased susceptibility to fatty liver disease. However, when fed a high-fat, fructose, and cholesterol diet, these mice had less inflammation and fibrosis, highlighting the stage-specific functions of SHMT2 in non-alcoholic fatty liver disease (NAFLD) pathogenesis [4]. In Burkitt lymphoma, inhibition of SHMT2 (by knockdown or pharmacological compounds) led to a reduction in intracellular glycine and formate levels, inhibiting the mTOR pathway and triggering autophagic degradation of the oncogenic transcription factor TCF3, which is essential for lymphoma cell survival [1].

In conclusion, SHMT2 is vital for one-carbon metabolism, playing roles in nucleotide and amino acid synthesis as well as immune signaling. Mouse models, especially SHMT2 KO/CKO models, have provided insights into its functions in diseases like NAFLD and Burkitt lymphoma, helping to understand the underlying mechanisms and potentially offering new therapeutic targets.

References:

1. Wilke, Anne C, Doebele, Carmen, Zindel, Alena, Zenz, Thorsten, Oellerich, Thomas. . SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma. In Blood, 139, 538-553. doi:10.1182/blood.2021012081. https://pubmed.ncbi.nlm.nih.gov/34624079/

2. Zeng, Yuanyuan, Zhang, Jie, Xu, Mengmeng, Chen, Nannan, Chin, Y Eugene. 2021. Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis. In Journal of Cancer, 12, 5888-5894. doi:10.7150/jca.60170. https://pubmed.ncbi.nlm.nih.gov/34476002/

3. Walden, Miriam, Tian, Lei, Ross, Rebecca L, Greenberg, Roger A, Zeqiraj, Elton. 2019. Metabolic control of BRISC-SHMT2 assembly regulates immune signalling. In Nature, 570, 194-199. doi:10.1038/s41586-019-1232-1. https://pubmed.ncbi.nlm.nih.gov/31142841/

4. Chen, Guohua, Zhou, Guoli, Zhai, Lidong, Mottillo, Emilio, Wang, Jian. 2024. SHMT2 reduces fatty liver but is necessary for liver inflammation and fibrosis in mice. In Communications biology, 7, 173. doi:10.1038/s42003-024-05861-y. https://pubmed.ncbi.nlm.nih.gov/38347107/