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

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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
Divisions:	Faculty of Science > Chemistry
Journal or Publication Title:	Nature Catalysis
Publisher:	Nature Research
ISSN:	2520-1158
Official Date:	November 2019
Dates:	Date Event November 2019 Published 14 October 2019 Available 17 August 2019 Accepted
Date of first compliant deposit:	27 September 2019
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
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID UNSPECIFIED Woolf Fisher Trust UNSPECIFIED UNSPECIFIED Cambridge Commonwealth European and International Trust UNSPECIFIED 2015/09188-8, 2017/50140-4 and 2018/00351-1 São Paulo Research Foundation UNSPECIFIED 141090/2016-2 CNPq (National Council for Scientific and Technological UNSPECIFIED UNSPECIFIED EPSRC UNSPECIFIED BB/J007250/1 BBSRC UNSPECIFIED UNSPECIFIED FAPESP–Warwick Joint Fund UNSPECIFIED

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