S-Adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-Alkylation

Iain J. W. Mckean, Joanna C. Sadler, Anibal Cuetos, Amina Frese, Luke D. Humphreys, Gideon Grogan, Paul A. Hoskisson, Glenn A. Burley

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)17583-17588
JournalAngewandte Chemie International Edition
Volume58
Issue number49
Early online date1 Oct 2019
DOIs
Publication statusE-pub ahead of print - 1 Oct 2019

Keywords / Materials (for Non-textual outputs)

  • alkylation
  • biocatalysis
  • coumarin
  • methyltransferase
  • S-adenosylmethionine

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