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Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids

Nature Chemical Biology volume 13, pages 467–469 (2017)Cite this article

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Abstract

The formation of C–C bonds in an enantioselective fashion to create complex polycyclic scaffolds in the hapalindole- and fischerindole- type alkaloids from Stigonematales cyanobacteria represents a compelling and urgent challenge in adapting microbial biosynthesis as a catalytic platform in drug development. Here we determine the biochemical basis for tri- and tetracyclic core formation in these secondary metabolites, involving a new class of cyclases that catalyze a complex cyclization cascade.

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Figure 1: Select hapalindole-type alkaloids.
Figure 2: Gene clusters identified from hapalindole producing strains.
Figure 3: In vitro assay involving recombinant cyclases to form hapalindole and fischerindole natural products.

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Acknowledgements

The authors thank the National Science Foundation under the CCI Center for Selective C-H Functionalization (CHE-1205646), the National Institutes of Health (CA70375 to R.M.W. and D.H.S.), and the Hans W. Vahlteich Professorship (to D.H.S.) for financial support. We are grateful to S. Carmeli and A. Raveh (Tel Aviv University) for Fischerella sp. IL-199-3-1, and J. Orjala (University of Illinois at Chicago) for Fischerella sp. SAG 46.79.

Author information

Authors and Affiliations

  1. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    Shasha Li, Andrew N Lowell, Sean A Newmister, Fengan Yu & David H Sherman

  2. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA

    Shasha Li & David H Sherman

  3. Department of Chemistry, Colorado State University, Fort Collins, Colorado, USA

    Robert M Williams

  4. University of Colorado Cancer Center, Aurora, Colorado, USA

    Robert M Williams

  5. Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA

    David H Sherman

  6. Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan, USA

    David H Sherman

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  1. Shasha Li
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  2. Andrew N Lowell
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  4. Fengan Yu
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Contributions

S.L. and D.H.S. designed the research. S.L. performed all experiments. A.N.L. synthesized the indole isonitrile. S.L., S.A.N., A.N.L. and D.H.S. conducted data analysis and interpretation. F.Y. performed bioinformatics analyses. S.L., A.N.L., D.H.S., and R.M.W. contributed to manuscript preparation.

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Correspondence to David H Sherman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–7 and Supplementary Figures 1–6 (PDF 1896 kb)

Dataset 1

Identity value table of Stig cyclases annotated from this study and public database, related to Supplementary Information_Figure 2 (PDF 1356 kb)

Supplementary Note

NMR Spectra (PDF 1564 kb)

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Li, S., Lowell, A., Newmister, S. et al. Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids. Nat Chem Biol 13, 467–469 (2017). https://doi.org/10.1038/nchembio.2327

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