Recycling Upstream Redox Enzymes Expands the Regioselectivity of Cycloaddition in Pseudo-Aspidosperma Alkaloid Biosynthesis

Mohamed O. Kamileen, Matthew D. Demars, Benke Hong, Yoko Nakamura, Christian Paetz, Benjamin R. Lichman, Prashant D. Sonawane, Lorenzo Caputi*, Sarah E. O'Connor

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Pages (from-to)19673–19679
Number of pages7
JournalJournal of the American Chemical Society
Issue number43
Early online date14 Oct 2022
Publication statusPublished - 2 Nov 2022

Bibliographical note

© 2022 The Authors
Funding 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.

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