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Reconstruction of the saframycin core scaffold defines dual Pictet-Spengler mechanisms

Nature Chemical Biology volume 6, pages 408–410 (2010)Cite this article

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Abstract

Saframycin A is a potent antitumor antibiotic with a unique pentacyclic tetrahydroisoquinoline scaffold. We found that the nonribosomal peptide synthetase SfmC catalyzes a seven-step transformation of readily synthesized dipeptidyl substrates with long acyl chains into a complex saframycin scaffold. Based on a series of enzymatic reactions, we propose a detailed mechanism involving the reduction of various peptidyl thioesters by a single R domain followed by iterative C domain–mediated Pictet-Spengler reactions.

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Figure 1: Proposed overall scheme for the pentacyclic core skeleton assembly.
Figure 2: SfmC-catalyzed reaction with the various dipeptidyl-CoA substrates 4a–e.

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Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) ((B)20310126 to H. Oikawa) and in part by a grant from Japan Science and Technology (JST) (Research for Promoting Technological Seeds 01-073 to H. Oikawa). A fellowship to K.K. from the JSPS is gratefully acknowledged. We thank Y. Kumaki and S. Oka (both of Hokkaido University) for obtaining NMR and mass data.

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Authors and Affiliations

  1. Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, Japan

    Kento Koketsu, Haruna Suda, Hiroki Oguri & Hideaki Oikawa

  2. School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

    Kenji Watanabe

Authors
  1. Kento Koketsu
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  2. Kenji Watanabe
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  3. Haruna Suda
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  4. Hiroki Oguri
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  5. Hideaki Oikawa
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Contributions

H. Oikawa and K.W. designed the research, and H. Oikawa wrote the manuscript. K.K. and H.S. synthesized the substrates for the enzymatic reactions. K.W. cloned the sfmC gene and optimized the expression conditions. K.K. prepared the deletion enzymes and performed all enzymatic reactions. H. Oguri advised on the research and made a significant contribution to a proposal of the reaction mechanism.

Corresponding author

Correspondence to Hideaki Oikawa.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–17 and Supplementary Tables 1 and 2 (PDF 1761 kb)

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Koketsu, K., Watanabe, K., Suda, H. et al. Reconstruction of the saframycin core scaffold defines dual Pictet-Spengler mechanisms. Nat Chem Biol 6, 408–410 (2010). https://doi.org/10.1038/nchembio.365

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