Xanthine Derivatives Reveal an Allosteric Binding Site in Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2)
| Autor: | Su-Ying Wu, Tsu Hsu, Weir-Torn Jiaang, Ching-Cheng Hsueh, Hsin-Huei Chang, Fang-Chun Kung, Cheng-Tai Lu, Yi-Hui Peng, Ching-Chuan Kuo, Lung-Chun Lee, Chih-Hsiang Huang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Allosteric regulation Xanthine Article Cofactor Structure-Activity Relationship chemistry.chemical_compound Downregulation and upregulation Aminohydrolases Drug Discovery Humans Enzyme Inhibitors MTHFD2 Gene Methylenetetrahydrofolate Dehydrogenase (NADP) Dose-Response Relationship Drug Molecular Structure biology Substrate (chemistry) Metabolism Multifunctional Enzymes Biochemistry chemistry biology.protein Molecular Medicine Uncompetitive inhibitor Allosteric Site |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 15, which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by 15. 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 15, 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|