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Diene incorporation by a dehydratase domain variant in modular polyketide synthases
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Hobson, Christian, Jenner, Matthew, Jian, Xinyun, Griffiths, Daniel, Roberts, Douglas M., Rey-Carrizo, Matias and Challis, Gregory L. (2022) Diene incorporation by a dehydratase domain variant in modular polyketide synthases. Nature Chemical Biology, 18 . pp. 1410-1416. doi:10.1038/s41589-022-01127-y ISSN 1552-4469.
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WRAP-Diene-incorporation-dehydratase-domain-variant-modular-polyketide-synthases-22.pdf - Accepted Version Embargoed item. Restricted access to Repository staff only until 15 September 2023. Contact author directly, specifying your specific needs. - Requires a PDF viewer. Download (355Kb) |
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WRAP-Supplementary-information-final-2-22.pdf - Supplemental Material Embargoed item. Restricted access to Repository staff only until 15 September 2023. Contact author directly, specifying your specific needs. - Requires a PDF viewer. Download (3598Kb) |
Official URL: https://doi.org/10.1038/s41589-022-01127-y
Abstract
Modular polyketide synthases (PKSs) are biosynthetic assembly lines that construct structurally diverse natural products with wide-ranging applications in medicine and agriculture. Various mechanisms contribute to structural diversification during PKS-mediated chain assembly, including dehydratase (DH) domain-mediated elimination of water from R and S-configured 3-hydroxy-thioesters to introduce E- and Z-configured carbon–carbon double bonds, respectively. Here we report the discovery of a DH domain variant that catalyzes the sequential elimination of two molecules of water from a (3R, 5S)-3,5-dihydroxy thioester during polyketide chain assembly, introducing a conjugated E,Z-diene into various modular PKS products. We show that the reaction proceeds via a (2E, 5S)-2-enoyl-5-hydroxy-thioester intermediate and involves an additional universally conserved histidine residue that is absent from the active site of most conventional DH domains. These findings expand the diverse range of chemistries mediated by DH-like domains in modular PKSs, highlighting the catalytic versatility of the double hotdog fold.
| Item Type: | Journal Article | ||||||||
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
| SWORD Depositor: | Library Publications Router | ||||||||
| Journal or Publication Title: | Nature Chemical Biology | ||||||||
| Publisher: | Springer Science and Business Media LLC | ||||||||
| ISSN: | 1552-4469 | ||||||||
| Official Date: | December 2022 | ||||||||
| Dates: |
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| Volume: | 18 | ||||||||
| Page Range: | pp. 1410-1416 | ||||||||
| DOI: | 10.1038/s41589-022-01127-y | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Reuse Statement (publisher, data, author rights): | “This version of the article has been accepted for publication, after peer review (when applicable) but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41589-022-01127-y Use of this Accepted Version is subject to the publisher’s Accepted Manuscript terms of use https://www.springernature.com/gp/open-research/policies/acceptedmanuscript-terms”." | ||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||
| Date of first compliant deposit: | 27 October 2022 | ||||||||
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