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    Single step syntheses of (1 S)-aryltetrahydroisoquinolines by norcoclaurine synthases

    Roddan, Rebecca and Keep, Nicholas H. and Sula, Altin (2020) Single step syntheses of (1 S)-aryltetrahydroisoquinolines by norcoclaurine synthases. Nature Communications 3 (170), ISSN 2041-1723.

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    Abstract

    The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic routes have been reported, the substrate scope is limited to certain structural motifs. The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynthesis, has been shown to perform stereoselective Pictet–Spengler reactions between dopamine and several carbonyl substrates. Here, benzaldehydes are explored as substrates and found to be accepted by both wild-type and mutant constructs of NCS. In particular, the variant M97V gives a range of (1 S)-aryl-THIQs in high yields (48–99%) and e.e.s (79–95%). A cocrystallised structure of the M97V variant with an active site reaction intermediate analogue is also obtained with the ligand in a pre-cyclisation conformation, consistent with (1 S)-THIQs formation. Selected THIQs are then used with catechol O-methyltransferases with exceptional regioselectivity. This work demonstrates valuable biocatalytic approaches to a range of (1 S)-THIQs

    Metadata

    Item Type: Article
    School: School of Science > Biological Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Nick Keep
    Date Deposited: 23 Nov 2020 10:56
    Last Modified: 14 Jun 2021 18:50
    URI: https://eprints.bbk.ac.uk/id/eprint/41152

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