S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

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 modifi...

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Bibliographic Details
Published in:Angewandte Chemie 2019-12, Vol.131 (49), p.17747-17752
Main Authors: McKean, Iain J. W., Sadler, Joanna C., Cuetos, Anibal, Frese, Amina, Humphreys, Luke D., Grogan, Gideon, Hoskisson, Paul A., Burley, Glenn A.
Format: Article
Language:English
Subjects:
Adenine
Alkylation
Alkylierung
Biokatalyse
Chemistry
Cofactors
Coumarin
Coupling (molecular)
Cumarin
Deoxyadenosine
Methionine
Methyltransferase
S-Adenosylmethionin
Substrates
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Summary: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. 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.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201908681