Adenylation Activity of Carboxylic Acid Reductases Enables the Synthesis of Amides

Alexander Wood, Nicholas Weise, Joseph D. Frampton, Mark Dunstan, Michael Hollas, Sasha Derrington, Richard C. Lloyd, Daniela Quaglia, Fabio Parmeggiani, David Leys, Nicholas Turner, Sabine Flitsch

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    Abstract

    Carboxylic acid reductases (CARs) catalyze the reduction of a broad range of carboxylic acids to aldehydes using the co-factors ATP and NADPH, and have become attractive biocatalysts for organic synthesis. Here we exploit our mechanistic understanding of CARs to expand their reaction scope, generating biocatalysts for amide bond formation from carboxylic acid and amine. After reaction engineering, CARs were found to have amidation activity for various acids and amines. Optimization of reaction conditions with respect to pH and temperature allowed for the synthesis of the anticonvulsant ilepcimide with up to 96% conversion. Mechanistic studies using site-directed mutagenesis suggest that following initial enzymatic adenylation of substrates, amidation of the carboxylic acid proceeds via direct reaction of the acyl adenylate with amine nucleophiles.
    Original languageEnglish
    Pages (from-to)14498-14501
    Number of pages4
    JournalAngewandte Chemie
    Volume56
    Issue number46
    Early online date11 Oct 2017
    DOIs
    Publication statusPublished - 13 Nov 2017

    Keywords

    • Amides
    • amidation
    • carboxylic acid reductase
    • Biocatalysis
    • amido synthetase

    Research Beacons, Institutes and Platforms

    • Manchester Institute of Biotechnology

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