S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation

McKean, Iain and Sadler, Joanna and Cuetos, Anibal and Frese, Amina and Humphreys, Luke and Grogan, Gideon and Hoskisson, Paul and Burley, Glenn (2019) S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation. Angewandte Chemie International Edition. ISSN 1433-7851

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    Abstract

    A tandem enzymatic strategy to enhance the scope of C-alkylation of small molecules via the in situ formation of S-adenosyl methionine (SAM) cofactor analogues is described. A solvent-exposed channel present in the SAM-forming enzyme SalL tolerates 5′-chloro-5′-deoxyadenosine (ClDA) analogues modified at the 2-position of the adenine nucleobase. Coupling SalL-catalyzed cofactor production with C-(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C-(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C-alkylation provides the basis to develop a late-stage enzymatic platform for the preparation of high value small molecules.