Nucleoside-modified AdoMet analogues for differential methyltransferase targeting.

Nicolas V Cornelissen, Freideriki Michailidou, Fabian Muttach, Kristina Rau, Andrea Rentmeister

Chemical communications (Cambridge, England) 2020 Feb 18

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Methyltransferases (MTases) modify a wide range of biomolecules using S-adenosyl-l-methionine (AdoMet) as the cosubstrate. Synthetic AdoMet analogues are powerful tools to site-specifically introduce a variety of functional groups and exhibit potential to be converted only by distinct MTases. Extending the size of the substituent at the sulfur/selenium atom provides selectivity among MTases but is insufficient to discriminate between promiscuous MTases. We present a panel of AdoMet analogues differing in the nucleoside moiety (NM-AdoMets). These NM-AdoMets were efficiently produced by a previously uncharacterized methionine adenosyltransferase (MAT) from methionine and ATP analogues, such as ITP and N6-propargyl-ATP. The N6-modification changed the relative activity of three representative MTases up to 13-fold resulting in discrimination of substrates for the methyl transfer and could also be combined with transfer of allyl and propargyl groups.

Citation

Nicolas V Cornelissen, Freideriki Michailidou, Fabian Muttach, Kristina Rau, Andrea Rentmeister. Nucleoside-modified AdoMet analogues for differential methyltransferase targeting. Chemical communications (Cambridge, England). 2020 Feb 18;56(14):2115-2118