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Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis

DOI: 10.1038/s41929-019-0351-2 DOI Help

Authors: Rory Little (University of Cambridge) , Fernanda C. R. Paiva (University of São Paulo) , Robert Jenkins (University of Warwick) , Hui Hong (University of Cambridge) , Yuhui Sun (Wuhan University) , Yuliya Demydchuk (University of Cambridge; Bicycle Therapeutics Limited) , Markiyan Samborskyy (University of Cambridge) , Manuela Tosin (University of Warwick) , Finian J. Leeper (University of Cambridge) , Marcio V. B. Dias (University of São Paulo; University of Warwick) , Peter F. Leadlay (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Catalysis , VOL 460

State: Published (Approved)
Published: October 2019

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.

Journal Keywords: Asymmetric catalysis; Biocatalysis; Biosynthesis; Enzymes; Structure elucidation

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography