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Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis
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Little, Rory, Paiva, Fernanda C. R., Jenkins, Robert, Hong, Hui, Sun, Yuhui, Demydchuk, Yuliya, Samborskyy, Markiyan, Tosin, Manuela, Leeper, Finian J., Dias, Marcio Vinicius Bertacine and Leadlay, Peter F. (2019) Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis. Nature Catalysis, 2 . pp. 1045-1054. doi:10.1038/s41929-019-0351-2 ISSN 2520-1158.
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WRAP-Unexpected enzyme-cycloaddition-polyether-antibiotic-biosynthesis-Dias-2019.pdf - Accepted Version - Requires a PDF viewer. Download (10Mb) | Preview |
Official URL: https://doi.org/10.1038/s41929-019-0351-2
Abstract
Enzymes that catalyse remarkable Diels–Alder-like [4+2] cyclizations have been previously implicated in the biosynthesis of spirotetronate and spirotetramate antibiotics. Biosynthesis of the polyether antibiotic tetronasin is not expected to require such steps, yet the tetronasin gene cluster encodes enzymes Tsn11 and Tsn15, which are homologous to authentic [4+2] cyclases. Here, we show that deletion of Tsn11 led to accumulation of a late-stage intermediate, in which the two central rings of tetronasin and four of its twelve asymmetric centres remain unformed. In vitro reconstitution showed that Tsn11 catalyses an apparent inverse-electron-demand hetero-Diels–Alder-like [4+2] cyclization of this species to form an unexpected oxadecalin compound that is then rearranged by Tsn15 to form tetronasin. To gain structural and mechanistic insight into the activity of Tsn15, the crystal structure of a Tsn15-substrate complex has been solved at 1.7 Å resolution.
| Item Type: | Journal Article | |||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | |||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Enzymes, Catalysis, Ring formation (Chemistry), Polyethers -- Biotechnology, Antibiotics -- Analysis, Biosynthesis -- Research | |||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Nature Catalysis | |||||||||||||||||||||||||||||||||
| Publisher: | Nature Research | |||||||||||||||||||||||||||||||||
| ISSN: | 2520-1158 | |||||||||||||||||||||||||||||||||
| Official Date: | November 2019 | |||||||||||||||||||||||||||||||||
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| Volume: | 2 | |||||||||||||||||||||||||||||||||
| Page Range: | pp. 1045-1054 | |||||||||||||||||||||||||||||||||
| DOI: | 10.1038/s41929-019-0351-2 | |||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 27 September 2019 | |||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 14 April 2020 | |||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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