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Sarpagan bridge enzyme has substrate-controlled cyclization and aromatization modes

Nature Chemical Biology volume 14, pages 760–763 (2018)Cite this article

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Abstract

Cyclization reactions that create complex polycyclic scaffolds are hallmarks of alkaloid biosynthetic pathways. We present the discovery of three homologous cytochrome P450s from three monoterpene indole alkaloid-producing plants (Rauwolfia serpentina, Gelsemium sempervirens and Catharanthus roseus) that provide entry into two distinct alkaloid classes, the sarpagans and the β-carbolines. Our results highlight how a common enzymatic mechanism, guided by related but structurally distinct substrates, leads to either cyclization or aromatization.

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Fig. 1: Sarpagan bridge enzyme candidate screening using combinatorial expression in N. benthamiana.
Fig. 2: The cyclization and aromatization catalytic function of recombinant RsSBE, GsSBE and CrAS depend on the substrate.

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  • 26 July 2019

    In the version of this article originally published, numbered compounds were not linked correctly to their respective compound pages. The error has been corrected in the HTML version of this paper.

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Acknowledgements

T.T.T.D. is grateful to the EMBO Long Term Fellowship ALTF 739–2015. J.F. gratefully acknowledges DFG postdoctoral funding (FR 3720/1-1). This work was supported by grants from the European Research Council (311363), BBSRC (BB/J004561/1) (S.E.O.) and from the Région Centre, France (BioPROPHARM, CatharSIS grants) (V.C.). We thank E. Poupon and L. Evanno (Univ. Paris-Sud) for their generous gift of polyneuridine aldehyde standard. Rauwolfia serpentina seeds were a generous gift from S. Hiremath, Karnataka University, India. D.-K. Ro (University of Calgary) generously provided pESC-Leu2d. Images of R. serpentina and C. roseus were provided by T. Nguyen (Ho Chi Minh City University of Science). We thank L. Caputi (John Innes Centre) for his assistance in building the homology model of CrAS and RsSBE and L. Hill and G. Saalbach of the Molecular Analysis platform at John Innes Centre for their assistance in metabolic analysis. We are grateful to D. Grzech for her assistance in cloning mutant constructs. We thank R. Hughes and M. Franceschetti (John Innes Centre) for preparing the modified TRBO vector.

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Author notes

  1. These authors contributed equally: Thu-Thuy T. Dang, Jakob Franke.

Authors and Affiliations

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

    Thu-Thuy T. Dang, Jakob Franke, Chloe Langley & Sarah E. O’Connor

  2. Université François-Rabelais de Tours, Biomolécules et Biotechnologies Végétales, Parc de Grandmont Tours, Tours, France

    Ines Soares Teto Carqueijeiro & Vincent Courdavault

Authors
  1. Thu-Thuy T. Dang
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  2. Jakob Franke
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  3. Ines Soares Teto Carqueijeiro
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  4. Chloe Langley
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  5. Vincent Courdavault
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  6. Sarah E. O’Connor
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Contributions

T.-T.T.D., J.F. and S.E.O. designed the experiments and wrote the manuscript. T.-T.T.D. characterized RsSBE, GsSBE and CrAS in vitro and in vivo, and performed in planta combinatorial assay and analysis. J.F. performed all substrate purification, synthesis and product characterizations. C.L. contributed to N. benthamiana work. I.S.T.C. and V.C. performed VIGS and localization experiments.

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Correspondence to Sarah E. O’Connor.

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Supplementary Figures 1–12, Supplementary Tables 1–4

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Dang, TT.T., Franke, J., Carqueijeiro, I.S.T. et al. Sarpagan bridge enzyme has substrate-controlled cyclization and aromatization modes. Nat Chem Biol 14, 760–763 (2018). https://doi.org/10.1038/s41589-018-0078-4

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