期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 49, 页码 17583-17588出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201908681
关键词
alkylation; biocatalysis; coumarin; methyltransferase; S-adenosylmethionine
资金
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/M016366/1, BB/N016378/1]
- GlaxoSmithKline (GSK)
- BBSRC [BB/P005578/1]
- GSK
- University of Strathclyde
- BBSRC [BB/R006857/1, BB/M016366/1, BB/N016378/1, 1722392, BB/P005578/1] Funding Source: UKRI
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.
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