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A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis

Nature Chemistry volume 9, pages 1235–1242 (2017)Cite this article

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Abstract

Bacterial meroterpenoids constitute an important class of natural products with diverse biological properties and therapeutic potential. The biosynthetic logic for their production is unknown and defies explanation via classical biochemical paradigms. A large subgroup of naphthoquinone-based meroterpenoids exhibits a substitution pattern of the polyketide-derived aromatic core that seemingly contradicts the established reactivity pattern of polyketide phenol nucleophiles and terpene diphosphate electrophiles. We report the discovery of a hitherto unprecedented enzyme-promoted α-hydroxyketone rearrangement catalysed by vanadium-dependent haloperoxidases to account for these discrepancies in the merochlorin and napyradiomycin class of meroterpenoid antibiotics, and we demonstrate that the α-hydroxyketone rearrangement is potentially a conserved biosynthetic reaction in this molecular class. The biosynthetic α-hydroxyketone rearrangement was applied in a concise total synthesis of naphthomevalin, a prominent member of the napyradiomycin meroterpenes, and sheds further light on the mechanism of this unifying enzymatic transformation.

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Figure 1: Bacterial THN-derived meroterpenes.
Figure 2: Mcl24-mediated reaction of pre-merochlorin (9).
Figure 3: Chemical chlorination of pre-merochlorin (9) or analogue 17.
Figure 4: Biomimetic total synthesis of (±)-naphthomevalin (1) via a thermal α-hydroxyketone rearrangement.
Figure 5: Theoretical and experimental studies on the thermally induced α-hydroxyketone rearrangement.
Figure 6: NapT8-, NapH3- and NapH1-coupled assays with synthetic 34.

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Acknowledgements

We are grateful to our University of California San Diego colleagues B. Duggan for assistance with NMR measurements and X. Tang for helpful discussions. We are also grateful to M. Ghadiri and L. J. Leman at The Scripps Research Institute for their help in the collection of CD measurements. S.D. acknowledges the Swiss National Science Foundation for a postdoctoral fellowship. This research was supported by the US National Institutes of Health (R01-AI047818) and the Australian Research Council (DP160103393), and was undertaken with the assistance of resources from the National Computational Infrastructure, which is supported by the Australian Government.

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Author notes

  1. Zachary D. Miles, Stefan Diethelm and Henry P. Pepper: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, 92093, California, USA

    Zachary D. Miles, Stefan Diethelm & Bradley S. Moore

  2. Department of Chemistry, The University of Adelaide, Adelaide, 5005, South Australia, Australia

    Henry P. Pepper, David M. Huang & Jonathan H. George

  3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, 92093, California, USA

    Bradley S. Moore

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Contributions

Z.D.M., S.D., H.P.P., J.H.G. and B.S.M. designed the study and wrote the manuscript with input from all of the authors. Z.D.M., S.D. and H.P.P. performed the experiments. D.M.H. performed the computational studies.

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Correspondence to Jonathan H. George or Bradley S. Moore.

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Miles, Z., Diethelm, S., Pepper, H. et al. A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis. Nature Chem 9, 1235–1242 (2017). https://doi.org/10.1038/nchem.2829

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