S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation. (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. Volume 131:Number 49(2019)
• Page Start: 17747
• Page End: 17752
• Publication Date: 2019-10-21
• Subjects: Alkylierung -- Biokatalyse -- Cumarin -- Methyltransferase -- S-Adenosylmethionin; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201908681
• Languages: English
• ISSNs: 0044-8249

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 : Eine enzymatische Tandemstrategie zur Erweiterung des Umfangs der C‐Alkylierung kleiner Moleküle durch Verknüpfung der Produktion von S‐Adenosylmethionin (SAM)‐Cofaktoranaloga mit C‐Methyl‐/Ethyltransfer auf Cumarinsubstrate, katalysiert durch die Methyltransferase (MTase) NovO, wird beschrieben. Im Vergleich zu Cofaktoren ohne Nukleobase‐Modifikationen werden C‐methylierte/ethylierte Cumarine mit höherer Ausbeute und größerem Substratumfang gebildet.