A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis

Joleen Masschelein, Paulina K. Sydor, Christian Hobson, Rhiannon Howe, Cerith Jones, Douglas M. Roberts, Zhong Ling Yap, Julian Parkhill, Eshwar Mahenthiralingam, Gregory L. Challis

    Allbwn ymchwil: Cyfraniad at gyfnodolynErthygladolygiad gan gymheiriaid

    23 Wedi eu Llwytho i Lawr (Pure)

    Crynodeb

    Polyketide synthases assemble diverse natural products with numerous important applications. The thioester intermediates in polyketide assembly are covalently tethered to acyl carrier protein domains of the synthase. Several mechanisms for polyketide chain release are known, contributing to natural product structural diversification. Here, we report a dual transacylation mechanism for chain release from the enacyloxin polyketide synthase, which assembles an antibiotic with promising activity against Acinetobacter baumannii. A non-elongating ketosynthase domain transfers the polyketide chain from the final acyl carrier protein domain of the synthase to a separate carrier protein, and a non-ribosomal peptide synthetase condensation domain condenses it with (1S,3R,4S)-3,4-dihydroxycyclohexane carboxylic acid. Molecular dissection of this process reveals that non-elongating ketosynthase domain-mediated transacylation circumvents the inability of the condensation domain to recognize the acyl carrier protein domain. Several 3,4-dihydroxycyclohexane carboxylic acid analogues can be employed for chain release, suggesting a promising strategy for producing enacyloxin analogues.
    Iaith wreiddiolSaesneg
    Tudalennau (o-i)906-912
    CyfnodolynNature Chemistry
    Cyfrol11
    Dynodwyr Gwrthrych Digidol (DOIs)
    StatwsCyhoeddwyd - 23 Medi 2019

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