Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase

dc.contributor.authorIyamu, Iredia D.
dc.contributor.authorVilseck, Jonah Z.
dc.contributor.authorYadav, Ravi
dc.contributor.authorNoinaj, Nicholas
dc.contributor.authorHuang, Rong
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2024-09-23T15:05:44Z
dc.date.available2024-09-23T15:05:44Z
dc.date.issued2022
dc.description.abstractNicotinamide 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.versionFinal published version
dc.identifier.citationIyamu 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.urihttps://hdl.handle.net/1805/43524
dc.language.isoen_US
dc.publisherWiley
dc.relation.isversionof10.1002/anie.202114813
dc.relation.journalAngewandte Chemie
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.sourcePublisher
dc.subjectBisubstrate analogues
dc.subjectBisubstrate inhibitors
dc.subjectCell-potent inhibitors
dc.subjectEnzymes
dc.subjectSAM analogues
dc.titleExploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase
dc.typeArticle
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