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A heme-dependent enzyme forms the nitrogen–nitrogen bond in piperazate

Nature Chemical Biology volume 13, pages 836–838 (2017)Cite this article

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Abstract

Molecules containing a nitrogen–nitrogen (N–N) linkage have a variety of structures and biological activities; however, no enzyme has yet been demonstrated to catalyze N–N bond formation in an organic molecule. Here we report that the heme-dependent enzyme KtzT from Kutzneria sp. 744 catalyzes N–N bond formation in the biosynthesis of piperazate, a building block for nonribosomal peptides.

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Figure 1: Select Piz-containing natural products and their biosynthetic gene clusters.
Figure 2: KtzT catalyzes N–N bond formation to give piperazate.
Figure 3: KtzT is a heme-dependent enzyme.

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References

  1. Blair, L.M. & Sperry, J. J. Nat. Prod. 76, 794–812 (2013).

    Article  CAS  Google Scholar 

  2. Le Goff, G. & Ouazzani, J. Bioorg. Med. Chem. 22, 6529–6544 (2014).

    Article  CAS  Google Scholar 

  3. Kumar, V., Kaur, K., Gupta, G.K. & Sharma, A.K. Eur. J. Med. Chem. 69, 735–753 (2013).

    Article  CAS  Google Scholar 

  4. Sugai, Y., Katsuyama, Y. & Ohnishi, Y. Nat. Chem. Biol. 12, 73–75 (2016).

    Article  CAS  Google Scholar 

  5. Winter, J.M., Jansma, A.L., Handel, T.M. & Moore, B.S. Angew. Chem. Int. Ed. Engl. 48, 767–770 (2009).

    Article  CAS  Google Scholar 

  6. Garg, R.P., Qian, X.L., Alemany, L.B., Moran, S. & Parry, R.J. Proc. Natl. Acad. Sci. USA 105, 6543–6547 (2008).

    Article  CAS  Google Scholar 

  7. Huang, Z., Wang, K.-K.A. & Van der Donk, W.A. Chem. Sci. 7, 5219–5223 (2016).

    Article  CAS  Google Scholar 

  8. Baunach, M., Ding, L., Bruhn, T., Bringmann, G. & Hertweck, C. Angew. Chem. Int. Ed. Engl. 52, 9040–9043 (2013).

    Article  CAS  Google Scholar 

  9. Guo, Y.-Y. et al. Org. Lett. 17, 6114–6117 (2015).

    Article  CAS  Google Scholar 

  10. Oelke, A.J., France, D.J., Hofmann, T., Wuitschik, G. & Ley, S.V. Nat. Prod. Rep. 28, 1445–1471 (2011).

    Article  CAS  Google Scholar 

  11. Ciufolini, M.A. & Xi, N. Chem. Soc. Rev. 27, 437–445 (1998).

    Article  CAS  Google Scholar 

  12. Handy, E.L. & Sello, J.K. Top. Heterocycl. Chem. http://dx.doi.org/10.1007/7081_2015_185 (2015).

  13. Neumann, C.S. et al. ChemBioChem 13, 972–976 (2012).

    Article  CAS  Google Scholar 

  14. Fujimori, D.G. et al. Proc. Natl. Acad. Sci. USA 104, 16498–16503 (2007).

    Article  Google Scholar 

  15. Du, Y.-L., Dalisay, D.S., Andersen, R.J. & Ryan, K.S. Chem. Biol. 20, 1002–1011 (2013).

    Article  CAS  Google Scholar 

  16. Qu, X. et al. Mol. Biosyst. 7, 852–861 (2011).

    Article  CAS  Google Scholar 

  17. Ma, J. et al. Angew. Chem. Int. Ed. Engl. 123, 7943–7948 (2011).

    Article  Google Scholar 

  18. Setser, J.W., Heemstra, J.R. Jr., Walsh, C.T. & Drennan, C.L. Biochemistry 53, 6063–6077 (2014).

    Article  CAS  Google Scholar 

  19. Lin, Y.-M. & Miller, M.J. J. Org. Chem. 64, 7451–7458 (1999).

    Article  CAS  Google Scholar 

  20. Williams, D.E. et al. Org. Lett. 13, 3936–3939 (2011).

    Article  CAS  Google Scholar 

  21. Beltrán, J. et al. Nat. Chem. Biol. 11, 598–605 (2015).

    Article  Google Scholar 

  22. Berry, E.A. & Trumpower, B.L. Anal. Biochem. 161, 1–15 (1987).

    Article  CAS  Google Scholar 

  23. Fu, R. et al. J. Biol. Chem. 286, 26541–26554 (2011).

    Article  CAS  Google Scholar 

  24. Filippova, E.V. et al. Proteins 79, 2578–2582 (2011).

    Article  CAS  Google Scholar 

  25. Kartal, B. et al. Nature 479, 127–130 (2011).

    Article  CAS  Google Scholar 

  26. Dietl, A. et al. Nature 527, 394–397 (2015).

    Article  CAS  Google Scholar 

  27. Barr, I. & Guo, F. Bio Protoc. 5, e1594 (2015).

    Article  Google Scholar 

  28. Heemstra, J.R. Jr., Walsh, C.T. & Sattely, E.S. J. Am. Chem. Soc. 131, 15317–15329 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank L.D. Eltis and E. Kuatsjah for use of an oxygen electrode. We are grateful to C. Drennan (MIT) for provision of pET28a-ktzI. This work was supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada. Y.-L.D. and M.A.H. were supported by Michael Smith Foundation for Health Research Trainee Awards, and K.S.R. is a Canadian Institutes of Health Research New Investigator.

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Authors and Affiliations

  1. Institute of Pharmaceutical Biotechnology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

    Yi-Ling Du

  2. Department of Chemistry, The University of British Columbia, Vancouver, BC, Canada

    Yi-Ling Du, Hai-Yan He, Melanie A Higgins & Katherine S Ryan

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  1. Yi-Ling Du
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  4. Katherine S Ryan
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Contributions

Y.-L.D. designed the study, performed experiments, analyzed data, and wrote the manuscript. H.-Y.H. directed synthetic work. M.A.H. carried out gel-filtration studies. K.S.R. designed the study and wrote the manuscript.

Corresponding author

Correspondence to Katherine S Ryan.

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Competing interests

Y.-L.D. and K.S.R. are on a provisional patent application, filed through the University of British Columbia (at which K.S.R. is employed), that is based on the results described here.

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Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–14 (PDF 4481 kb)

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Du, YL., He, HY., Higgins, M. et al. A heme-dependent enzyme forms the nitrogen–nitrogen bond in piperazate. Nat Chem Biol 13, 836–838 (2017). https://doi.org/10.1038/nchembio.2411

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