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 journalArticle

6 Citations (Scopus)
4 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)17583-17588
Number of pages6
JournalAngewandte Chemie International Edition
Volume58
Issue number49
Early online date21 Oct 2019
DOIs
Publication statusPublished - 2 Dec 2019

Keywords

  • alkylation
  • methyltransferase
  • coumarin
  • biocatalysis

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