Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase
dc.contributor.author | Iyamu, Iredia D. | |
dc.contributor.author | Vilseck, Jonah Z. | |
dc.contributor.author | Yadav, Ravi | |
dc.contributor.author | Noinaj, Nicholas | |
dc.contributor.author | Huang, Rong | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | |
dc.date.accessioned | 2024-09-23T15:05:44Z | |
dc.date.available | 2024-09-23T15:05:44Z | |
dc.date.issued | 2022 | |
dc.description.abstract | Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell-potent NNMT bisubstrate inhibitor II399, demonstrating a Ki of 5.9 nM in a biochemical assay and a cellular IC50 value of 1.9 μM. The inhibition mechanism and cocrystal structure confirmed II399 engages both the substrate and cofactor binding pockets. Computational modeling and binding data reveal a balancing act between enthalpic and entropic components that lead to II399′s low nM binding affinity. Notably, II399 is 1 000-fold more selective for NNMT than closely related methyltransferases. We expect that II399 would serve as a valuable probe to elucidate NNMT biology. Furthermore, this strategy provides the first case of introducing unconventional SAM mimics, which can be adopted to develop cell-potent inhibitors for other SAM-dependent methyltransferases. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Iyamu ID, Vilseck JZ, Yadav R, Noinaj N, Huang R. Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase. Angewandte Chemie International Edition. 2022;61(16):e202114813. doi:10.1002/anie.202114813 | |
dc.identifier.uri | https://hdl.handle.net/1805/43524 | |
dc.language.iso | en_US | |
dc.publisher | Wiley | |
dc.relation.isversionof | 10.1002/anie.202114813 | |
dc.relation.journal | Angewandte Chemie | |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | en |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0 | |
dc.source | Publisher | |
dc.subject | Bisubstrate analogues | |
dc.subject | Bisubstrate inhibitors | |
dc.subject | Cell-potent inhibitors | |
dc.subject | Enzymes | |
dc.subject | SAM analogues | |
dc.title | Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase | |
dc.type | Article |