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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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Official URL: https://doi.org/10.1038/s41929-019-0351-2

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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
Subjects: Q Science > QD Chemistry
Q Science > QP Physiology
R Medicine > RS Pharmacy and materia medica
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
Dates:
DateEvent
November 2019Published
14 October 2019Available
17 August 2019Accepted
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:
Project/Grant IDRIOXX Funder NameFunder ID
UNSPECIFIEDWoolf Fisher Trusthttps://www.woolffishertrust.co.nz/
UNSPECIFIEDCambridge Commonwealth, European and International Trusthttp://dx.doi.org/10.13039/501100003343
2015/09188-8Fundação de Amparo à Pesquisa do Estado de São PauloUNSPECIFIED
141090/2016-2Conselho Nacional de Desenvolvimento Científico e Tecnológicohttp://dx.doi.org/10.13039/501100003593
DTA PhD studentship[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/J007250/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
SPRINT awardFundação de Amparo à Pesquisa do Estado de São PauloUNSPECIFIED
2017/50140-4Fundação de Amparo à Pesquisa do Estado de São PauloUNSPECIFIED
2018/00351-1Fundação de Amparo à Pesquisa do Estado de São PauloUNSPECIFIED
SPRINT awardUniversity of Warwickhttp://dx.doi.org/10.13039/501100000741

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