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

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Masschelein, Joleen, Sydor, Paulina K., Hobson, Christian, Howe, Rhiannon, Jones, Cerith, Roberts, Douglas M., Zhong, Ling Yap, Parkhill, Julian, Mahenthiralingam, Eshwar and Challis, Gregory L. (2019) A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis. Nature Chemistry, 11 . 906-912 . doi:10.1038/s41557-019-0309-7 ISSN 1755-4330.

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Official URL: http://dx.doi.org/10.1038/s41557-019-0309-7

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Abstract

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.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH): Polyketides, Biosynthesis, Organic compounds -- Synthesis, Antibiotics -- Synthesis
Journal or Publication Title: Nature Chemistry
Publisher: Nature Publishing Group
ISSN: 1755-4330
Official Date: October 2019
Dates:
DateEvent
October 2019Published
23 September 2019Available
12 July 2019Accepted
Volume: 11
Page Range: 906-912
DOI: 10.1038/s41557-019-0309-7
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Date of first compliant deposit: 8 August 2019
Date of first compliant Open Access: 23 March 2020
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
BB/L021692/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/K002341/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
656067Marie Skłodowska-Curie ActionsUNSPECIFIED
UNSPECIFIEDResearch Foundation FlandersUNSPECIFIED
UNSPECIFIEDUniversity of Warwick. Institute of Advanced Studyhttp://viaf.org/viaf/123145858003223022265
BB/M017982/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
WM130033[RS] Royal Societyhttp://dx.doi.org/10.13039/501100000288
UNSPECIFIEDCardiff Undergraduate Research Opportunities ProgrammeUNSPECIFIED
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