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S ‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C ‐Alkylation
Author(s) -
McKean Iain J. W.,
Sadler Joanna C.,
Cuetos Anibal,
Frese Amina,
Humphreys Luke D.,
Grogan Gideon,
Hoskisson Paul A.,
Burley Glenn A.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201908681
Subject(s) - chemistry , alkylation , cofactor , nucleobase , stereochemistry , small molecule , enzyme , combinatorial chemistry , catalysis , biochemistry , dna
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.