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

    Research output: Contribution to journalArticlepeer-review

    37 Downloads (Pure)


    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.
    Original languageEnglish
    Pages (from-to)906-912
    JournalNature Chemistry
    Publication statusPublished - 23 Sept 2019


    • Antimicrobials
    • BIosynthesis
    • Multienzyme complexes
    • Natural products


    Dive into the research topics of 'A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis'. Together they form a unique fingerprint.

    Cite this