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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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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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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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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DOI: https://doi.org/10.1038/nchembio.317
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