S-Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C-Alkylation

Gideon James Grogan, Iain McKean, Joanna Sadler, Anibal Cuetos, Amina Frese, Luke Humphreys, Paul Hoskisson, Glenn Burley

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A tandem enzymatic strategy to enhance the scope of Calkylation of small molecules via the in situ formation of S-adenosyl methionine (SAM) cofactor analogues is described. A solventexposed channel present in the SAM-forming enzyme SalL tolerates 5'-chloro-5’-deoxyadenosine (ClDA) analogues modified at the 2position 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 which influence C-alkylation provides the basis to develop a late-stage enzymatic platform for the preparation of high value small molecules
Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalAngewandte Chemie International Edition
Early online date1 Oct 2019
Publication statusPublished - 2 Dec 2019

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