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Molecules. 2019 Dec 8;24(24). pii: E4492. doi: 10.3390/molecules24244492.

Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor.

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Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Rua Arcturus 3, São Bernardo do Campo, SP 09606-070, Brazil.
Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, 101 College St., Suite 700, Toronto, ON M5G 1L7, Canada.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.


Protein methyltransferases (PMTs) are enzymes involved in epigenetic mechanisms, DNA repair, and other cellular machineries critical to cellular identity and function, and are an important target class in chemical biology and drug discovery. Central to the enzymatic reaction is the transfer of a methyl group from the cofactor S-adenosylmethionine (SAM) to a substrate protein. Here we review how the essentiality of SAM for catalysis is exploited by chemical inhibitors. Occupying the cofactor binding pocket to compete with SAM can be hindered by the hydrophilic nature of this site, but structural studies of compounds now in the clinic revealed that inhibitors could either occupy juxtaposed pockets to overlap minimally, but sufficiently with the bound cofactor, or induce large conformational remodeling leading to a more druggable binding site. Rather than competing with the cofactor, other inhibitors compete with the substrate and rely on bound SAM, either to allosterically stabilize the substrate binding site, or for direct SAM-inhibitor interactions.


S-adenosylmethionine; inhibitors; mechanism of action; methyltransferases

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