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Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy

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Abstract

Two previously undetected enzymes involved in morphine biosynthesis and unique among plants to opium poppy have been identified as non-heme dioxygenases, in contrast to the functionally analogous cytochrome P450s found in mammals. We used functional genomics to isolate thebaine 6-O-demethylase (T6ODM) and codeine O-demethylase (CODM), the only known 2-oxoglutarate/Fe(II)-dependent dioxygenases that catalyze O-demethylation. Virus-induced gene silencing of T6ODM and CODM in opium poppy efficiently blocked metabolism at thebaine and codeine, respectively.

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Figure 1: Extracted ion chromatograms showing the substrates and products of T6ODM and CODM enzyme assays.
Figure 2: Virus-induced gene silencing analysis.

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References

  1. Ziegler, J. & Facchini, P.J. Annu. Rev. Plant Biol. 59, 735–769 (2008).

    Article  CAS  Google Scholar 

  2. Zhu, W. Med. Sci. Monit. 14, SC15–SC18 (2008).

    CAS  PubMed  Google Scholar 

  3. Grobe, N. et al. J. Biol. Chem. 284, 24425–24431 (2009).

    Article  CAS  Google Scholar 

  4. Unterlinner, B., Lenz, R. & Kutchan, T.M. Plant J. 18, 465–475 (1999).

    Article  CAS  Google Scholar 

  5. Grothe, T., Lenz, R. & Kutchan, T.M. J. Biol. Chem. 276, 30717–30723 (2001).

    Article  CAS  Google Scholar 

  6. Millgate, A.G. et al. Nature 431, 413–414 (2004).

    Article  CAS  Google Scholar 

  7. Nyman, U. Hereditas 89, 43–50 (1978).

    Article  CAS  Google Scholar 

  8. Hagel, J.M., Weljie, A.M., Vogel, H.J. & Facchini, P.J. Plant Physiol. 147, 1805–1821 (2008).

    Article  CAS  Google Scholar 

  9. Cotterill, P. Method of altering the alkaloid composition in poppy plants. International patent WO/2005/107436 (2005).

  10. Wilmouth, R.C. et al. Structure 10, 93–103 (2002).

    Article  CAS  Google Scholar 

  11. Lister, D.L., Kanungo, G., Rathbone, D.A. & Bruce, N.C. FEMS Microbiol. Lett. 181, 137–144 (1999).

    Article  CAS  Google Scholar 

  12. Craig, D.H., Moody, P.C.E., Bruce, N.C. & Scrutton, N.S. Biochemistry 37, 7598–7607 (1998).

    Article  CAS  Google Scholar 

  13. Ishida, T., Yano, M. & Toki, S. Drug Metab. Dispos. 19, 895–899 (1991).

    CAS  PubMed  Google Scholar 

  14. Tiainen, P., Myllyharju, J. & Koivunen, P. J. Biol. Chem. 280, 1142–1148 (2005).

    Article  CAS  Google Scholar 

  15. Nielsen, B., Röe, J. & Brochmann-Hanssen, E. Planta Med. 48, 205–206 (1983).

    Article  CAS  Google Scholar 

  16. Brochmann-Hanssen, E. Planta Med. 50, 343–345 (1984).

    Article  CAS  Google Scholar 

  17. De Carolis, E. & De Luca, V. Phytochemistry 36, 1093–1107 (1994).

    Article  CAS  Google Scholar 

  18. Hausinger, R.P. Crit. Rev. Biochem. Mol. Biol. 39, 21–68 (2004).

    Article  CAS  Google Scholar 

  19. Clifton, I.J. et al. J. Inorg. Biochem. 100, 644–669 (2006).

    Article  CAS  Google Scholar 

  20. Loenarz, C. & Schofield, C.J. Nat. Chem. Biol. 4, 152–156 (2008).

    Article  CAS  Google Scholar 

  21. Rapoport, R., Hanukoglu, I. & Sklan, D. Anal. Biochem. 218, 309–313 (1994).

    Article  CAS  Google Scholar 

  22. International Narcotics Control Board. Narcotic drugs: estimated world requirements for 2007; statistics for 2005 (E/INCB/2006/2). (United Nations Publications, 2006).

  23. Hawkins, K.M. & Smolke, C.D. Nat. Chem. Biol. 4, 564–573 (2008).

    Article  CAS  Google Scholar 

  24. Minami, H. et al. Proc. Natl. Acad. Sci. USA 105, 7393–7398 (2008).

    Article  CAS  Google Scholar 

  25. Parker, H.I., Blaschke, G. & Rapoport, H. J. Am. Chem. Soc. 94, 1276–1282 (1972).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to D. Kumar (Yale University) for the pTRV1 and pTRV2 vectors, V. Irish (Yale University) for the pTRV2-PapPDS construct, the Canadian National Research Council Plant Biotechnology Institute for hosting our sequence data on their FIESTA2 annotation platform, and Sanofi-Aventis for the gift of the opium poppy varieties and the alkaloid standards used in this work. We also thank K. Zulak, R. Bourgault and J. Ziegler for technical assistance with cDNA library construction, microarray preparation and mass spectrometry, respectively. J.M.H. is the recipient of an Alberta Ingenuity Graduate Scholarship. Funding for this work was provided through a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada and a Canada Research Chair in Plant Metabolic Processes Biotechnology, both awarded to P.J.F.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada

    Jillian M Hagel & Peter J Facchini

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  1. Jillian M Hagel
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  2. Peter J Facchini
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J.M.H. and P.J.F. contributed equally to all aspects of the experimental design and execution, and the preparation of the manuscript.

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Correspondence to Peter J Facchini.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–13, Supplementary Tables 1–3 and Supplementary Methods (PDF 1475 kb)

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Hagel, J., Facchini, P. Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy. Nat Chem Biol 6, 273–275 (2010). https://doi.org/10.1038/nchembio.317

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