Diene incorporation by a dehydratase domain variant in modular polyketide synthases

Christian Hobson, Matthew Jenner, Xinyun Jian, Daniel Griffiths, Douglas M. Roberts, Matias Rey-Carrizo, Gregory L. Challis

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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. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)1410–1416
Number of pages7
JournalNature Chemical Biology
Issue number12
Publication statusPublished - Dec 2022

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