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A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units

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Ray, Lauren, Valentic, Timothy R., Miyazawa, Takeshi, Withall, David M., Song, Lijiang, Milligan, Jacob C., Osada, Hiroyuki, Takahashi, Shunji, Tsai, Shiou-Chuan and Challis, Gregory L. (2016) A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units. Nature Communications, 7 . 13609. doi:10.1038/ncomms13609 ISSN 2041-1723.

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Official URL: http://dx.doi.org/10.1038/ncomms13609

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Abstract

Type I modular polyketide synthases assemble diverse bioactive natural products. Such multienzymes typically use malonyl and methylmalonyl-CoA building blocks for polyketide chain assembly. However, in several cases more exotic alkylmalonyl-CoA extender units are also known to be incorporated. In all examples studied to date, such unusual extender units are biosynthesized via reductive carboxylation of α, β-unsaturated thioesters catalysed by crotonyl-CoA reductase/carboxylase (CCRC) homologues. Here we show using a chemically-synthesized deuterium-labelled mechanistic probe, and heterologous gene expression experiments that the unusual alkylmalonyl-CoA extender units incorporated into the stambomycin family of polyketide antibiotics are assembled by direct carboxylation of medium chain acyl-CoA thioesters. X-ray crystal structures of the unusual β-subunit of the acyl-CoA carboxylase (YCC) responsible for this reaction, alone and in complex with hexanoyl-CoA, reveal the molecular basis for substrate recognition, inspiring the development of methodology for polyketide bio-orthogonal tagging via incorporation of 6-azidohexanoic acid and 8-nonynoic acid into novel stambomycin analogues.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH): Polyketides -- Synthesis, Biosynthesis
Journal or Publication Title: Nature Communications
Publisher: Nature Publishing Group
ISSN: 2041-1723
Official Date: 21 November 2016
Dates:
DateEvent
21 November 2016Published
19 October 2016Accepted
Volume: 7
Article Number: 13609
DOI: 10.1038/ncomms13609
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 31 March 2017
Date of first compliant Open Access: 31 March 2017
Funder: Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Royal Society of Chemistry (Great Britain), Biotica Technology Ltd, National Institutes of Health (U.S.) (NIH), Nihon Gakujutsu Shinkōkai [Japan Society for the Promotion of Science] (NGS), United States. Department of Energy. Office of Basic Energy Sciences (OBES)
Grant number: R01 GM100305, R01 GM076330 (NIH), E-AC02-05CH11231 (OBES)

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