Methionine adenosyltransferase 2A (MAT2A), also known as MAT2α, is a rate-limiting enzyme in the methionine cycle. It mainly catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphate (ATP). Through controlling the balance of the cellular methionine metabolite pool, MAT2A regulates crucial steps during metabolism and the epigenetic control of transcription [1,3].

In MTAP-deleted cancer cells, MAT2A was identified as a synthetic lethal target. Inhibiting MAT2A substantially reduces SAM levels, shows antiproliferative activity, and is mechanistically linked to reduced PRMT5 activity and splicing perturbations, leading to DNA damage and mitotic defects [2]. In H3K27M mutant glioma, MAT2A presents a therapeutic vulnerability. Depletion of MAT2A induces global depletion of H3K36me3, perturbing oncogenic and developmental transcriptional programs [4]. In osteosarcoma, MAT2A inhibits ferroptosis, and knockdown of MAT2A promotes ferroptosis by regulating the STAT3/SLC7A11 axis [5].

In conclusion, MAT2A is crucial for multiple biological processes, especially in metabolism and epigenetic regulation. Studies on MAT2A using gene-knockout or conditional-knockout models have revealed its significance in cancer and other diseases, providing potential therapeutic targets. In cancer, especially in MTAP-deleted and H3K27M mutant cancers, MAT2A inhibition shows promise as a treatment strategy [2,4].

References:

1. Li, Chunzheng, Gui, Gang, Zhang, Li, Zhou, Chen, Zha, Xiaoming. 2022. Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors. In Journal of medicinal chemistry, 65, 9531-9547. doi:10.1021/acs.jmedchem.2c00395. https://pubmed.ncbi.nlm.nih.gov/35796517/

2. Kalev, Peter, Hyer, Marc L, Gross, Stefan, Marks, Kevin M, Marjon, Katya. 2021. MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage. In Cancer cell, 39, 209-224.e11. doi:10.1016/j.ccell.2020.12.010. https://pubmed.ncbi.nlm.nih.gov/33450196/

3. Pulous, Fadi E, Steurer, Barbara, Pun, Frank W, Ren, Feng, Zhavoronkov, Alex. 2024. MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer. In Drug discovery today, 29, 104189. doi:10.1016/j.drudis.2024.104189. https://pubmed.ncbi.nlm.nih.gov/39306235/

4. Golbourn, Brian J, Halbert, Matthew E, Halligan, Katharine, Mack, Stephen C, Agnihotri, Sameer. 2022. Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome. In Nature cancer, 3, 629-648. doi:10.1038/s43018-022-00348-3. https://pubmed.ncbi.nlm.nih.gov/35422502/

5. Xia, Shuchi, Liang, Yun, Shen, Yuqing, Zhong, Wuxue, Ma, Yiqun. 2023. MAT2A inhibits the ferroptosis in osteosarcoma progression regulated by miR-26b-5p. In Journal of bone oncology, 41, 100490. doi:10.1016/j.jbo.2023.100490. https://pubmed.ncbi.nlm.nih.gov/37457846/