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Structural basis of cycloaddition in biosynthesis of iboga and aspidosperma alkaloids

Nature Chemical Biology volume 16, pages 383–386 (2020)Cite this article

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Abstract

Cycloaddition reactions generate chemical complexity in a single step. Here we report the crystal structures of three homologous plant-derived cyclases involved in the biosynthesis of iboga and aspidosperma alkaloids. These enzymes act on the same substrate, named angryline, to generate three distinct scaffolds. Mutational analysis reveals how these highly similar enzymes control regio- and stereo-selectivity.

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Fig. 1: Biosynthesis of aspidosperma and iboga alkaloids.
Fig. 2: Crystal structures of CS, TS and CorS.

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Data availability

Structures have been deposited at the Protein Data Bank under the accession codes 6RJ8 (coronaridine synthase), 6RS4 (tabersonine synthase) and 6RT8 (catharanthine synthase).

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Acknowledgements

S.E.O. acknowledges ERC (788301). J.F. acknowledges financial support by the SMART BIOTECS alliance between the Technische Universität Braunschweig and the Leibniz Universität Hannover, supported by the Ministry for Science and Culture (MWK) of Lower Saxony, Germany. We acknowledge Diamond Light Source for access to beamline I03 under proposal MX13467 with support from the European Community’s Seventh Framework Program (No. FP7/2007–2013) under Grant Agreement No. 283570 (BioStruct-X).

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Author notes

  1. These authors contributed equally: Lorenzo Caputi, Jakob Franke.

Authors and Affiliations

  1. Max Planck Institute of Chemical Ecology, Department of Natural Product Biosynthesis, Jena, Germany

    Lorenzo Caputi & Sarah E. O’Connor

  2. Leibniz University Hannover, Centre for Biomolecular Drug Research, Hannover, Germany

    Jakob Franke

  3. John Innes Centre, Department of Biological Chemistry, Norwich Research Park, Norwich, UK

    Kate Bussey, Scott C. Farrow, Clare E. M. Stevenson & David M. Lawson

  4. Laboratorio de Ciencias Quimicas-UENF-Campos dos Goytacazes-RJ, Campos dos Goytacazes, Brazil

    Ivo Jose Curcino Vieira

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  1. Lorenzo Caputi
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Contributions

L.C. and S.E.O. conceived the project. D.M.L. managed all crystallography experiments. D.M.L., L.C., S.C.F. and C.E.M.S solved the crystal structures. L.C. and S.C.F. performed all biochemical experiments. K.B. and I.J.C.V. isolated substrates and products. J.F. solved the structure of the enzymatic substrates and developed the enzymatic mechanisms.

Corresponding authors

Correspondence to David M. Lawson or Sarah E. O’Connor.

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The authors declare no competing interests.

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Supplementary Information

Supplementary Tables 1–4, Figs. 1–25 and Note.

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Caputi, L., Franke, J., Bussey, K. et al. Structural basis of cycloaddition in biosynthesis of iboga and aspidosperma alkaloids. Nat Chem Biol 16, 383–386 (2020). https://doi.org/10.1038/s41589-019-0460-x

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