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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
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Official URL: http://dx.doi.org/10.1038/ncomms13609
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 > 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: |
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| Date of first compliant deposit: | 31 March 2017 | ||||||
| Volume: | 7 | ||||||
| Article Number: | 13609 | ||||||
| DOI: | 10.1038/ncomms13609 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Open Access | ||||||
| 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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