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

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 1433-7851

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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.

    Creators(s): 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.;
    Item type:Article
    ID code:70079
    Keywords:alkylation, methyltransferase, coumarin, biocatalysis, Chemistry, Chemistry(all)
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Technology and Innovation Centre > Bionanotechnology
    Depositing user: Pure Administrator
    Date deposited:10 Oct 2019 14:24
    Last modified:22 Jan 2021 04:40
    URI:https://strathprints.strath.ac.uk/id/eprint/70079
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