S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation

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McKean, Iain J. W. and Sadler, Joanna C. and Cuetos, Anibal and Frese, Amina and Humphreys, Luke D. and Grogan, Gideon and Hoskisson, Paul A. and Burley, Glenn A. (2019) S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation. Angewandte Chemie International Edition, 58 (49). pp. 17583-17588. ISSN 1521-3773 (https://doi.org/10.1002/anie.201908681)

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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.

ORCID iDs

McKean, Iain J. W. ORCID logoORCID: https://orcid.org/0000-0002-4970-1508, Sadler, Joanna C. ORCID logoORCID: https://orcid.org/0000-0002-8442-0760, Cuetos, Anibal, Frese, Amina, Humphreys, Luke D., Grogan, Gideon, Hoskisson, Paul A. ORCID logoORCID: https://orcid.org/0000-0003-4332-1640 and Burley, Glenn A.;
CORE (COnnecting REpositories)