S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation. Issue 49 (21st October 2019)

• Record Type: Journal Article
• Authors: McKean, Iain J. W.; Sadler, Joanna C.; Cuetos, Anibal; Frese, Amina; Humphreys, Luke D.; Grogan, Gideon; Hoskisson, Paul A.; Burley, Glenn A.
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 49(2019)
• Page Start: 17583
• Page End: 17588
• Publication Date: 2019-10-21
• Subjects: alkylation -- biocatalysis -- coumarin -- methyltransferase -- S-adenosylmethionine; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201908681
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : A tandem enzymatic strategy to enhance the scope of C ‐alkylation of small molecules via coupling the production of S ‐adenosyl methionine (SAM) cofactor analogues with C ‐(m)ethyl transfer to coumarin substrates, catalyzed by the methyltransferase (MTase) NovO, is described. This forms C ‐(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications.