Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350 Taiwan, ROC.
Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406, Taiwan, ROC.
J Med Chem. 2021 Aug 12;64(15):11288-11301. doi: 10.1021/acs.jmedchem.1c00663. Epub 2021 Aug 2.
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in one-carbon metabolism. The MTHFD2 gene is upregulated in various cancers but very low or undetectable in normal proliferating cells, and therefore a potential target for cancer treatment. In this study, we present the structure of MTHFD2 in complex with xanthine derivative , which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by . Allosteric inhibitors often provide good selectivity and, indeed, xanthine derivatives are highly selective for MTHFD2. Moreover, several conformational changes were observed upon the binding of , which impeded the binding of the cofactor and phosphate to MTHFD2. To the best of our knowledge, this is the first study to identify allosteric inhibitors targeting the MTHFD family and our results would provide insights on the inhibition mechanism of MTHFD proteins and the development of novel inhibitors.
亚甲基四氢叶酸脱氢酶 2（MTHFD2）在一碳代谢中发挥重要作用。MTHFD2 基因在各种癌症中上调，但在正常增殖细胞中非常低或检测不到，因此是癌症治疗的潜在靶点。在这项研究中，我们展示了 MTHFD2 与黄嘌呤衍生物复合物的结构，该衍生物别构结合 MTHFD2 并与底物类似物共存。动力学研究表明 MTHFD2 被 非竞争抑制。别构抑制剂通常具有良好的选择性，事实上，黄嘌呤衍生物对 MTHFD2 具有高度选择性。此外，在结合 时观察到几种构象变化，这阻碍了辅因子和磷酸盐与 MTHFD2 的结合。据我们所知，这是首次鉴定针对 MTHFD 家族的别构抑制剂的研究，我们的结果将为 MTHFD 蛋白的抑制机制和新型抑制剂的开发提供见解。
