Abstract
Nature uses cycloaddition reactions to generate complex natural product scaffolds. Dehydrosecodine is a highly reactive biosynthetic intermediate that undergoes cycloaddition to generate several alkaloid scaffolds that are the precursors to pharmacologically important compounds such as vinblastine and ibogaine. Here we report how dehydrosecodine can be subjected to redox chemistry, which in turn allows cycloaddition reactions with alternative regioselectivity. By incubating dehydrosecodine with reductase and oxidase biosynthetic enzymes that act upstream in the pathway, we can access the rare pseudoaspidosperma alkaloids pseudo-tabersonine and pseudo-vincadifformine, both in vitro and by reconstitution in the plant Nicotiana benthamiana from an upstream intermediate. We propose a stepwise mechanism to explain the formation of the pseudo-tabersonine scaffold by structurally characterizing enzyme intermediates and by monitoring the incorporation of deuterium labels. This discovery highlights how plants use redox enzymes to enantioselectively generate new scaffolds from common precursors.
Original language | English |
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Pages (from-to) | 19673–19679 |
Number of pages | 7 |
Journal | Journal of the American Chemical Society |
Volume | 144 |
Issue number | 43 |
Early online date | 14 Oct 2022 |
DOIs | |
Publication status | Published - 2 Nov 2022 |
Bibliographical note
© 2022 The AuthorsFunding Information:
We would like to thank Chloe Langley for useful discussions on this work, Delia Ayled Serna Guerrero, Sarah Heinicke, and Maritta Kunert for assistance with mass spectrometry, and members of the Max Planck Institute for Chemical Ecology Research Green House for providing and taking care of Nicotiana benthamiana plants. We gratefully acknowledge the Max Planck Society and the European Research Council (788301) for funding. B.H. acknowledges the Humboldt Foundation.
Funding Information:
Open access funded by Max Planck Society.