The isomerization of neopinone to codeinone is a critical step in the biosynthesis of opiate alkaloids in opium poppy. Previously assumed to be spontaneous, the process is in fact catalyzed enzymatically by neopinone isomerase (NISO). Without NISO the primary metabolic products in the plant, in engineered microbes and in vitro are neopine and neomorphine, which are structural isomers of codeine and morphine, respectively. Inclusion of NISO in yeast strains engineered to convert thebaine to natural or semisynthetic opiates dramatically enhances formation of the desired products at the expense of neopine and neomorphine accumulation. Along with thebaine synthase, NISO is the second member of the pathogenesis-related 10 (PR10) protein family recently implicated in the enzymatic catalysis of a presumed spontaneous conversion in morphine biosynthesis.
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We are grateful to L. Brechenmacher (Southern Alberta Mass Spectrometry Centre, University of Calgary) for assistance with the proteomics analysis. We acknowledge the expert genome sequencing and preliminary assembly services provided by the McGill University-Genome Québec Innovation Centre. This work was supported by funds awarded through the Industrial Research Assistance Program (IRAP; Project 86155) operated by the National Research Council of Canada to Epimeron Inc.
A patent application related to this work has been filed (PCT/CA2018/051520).
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Dastmalchi, M., Chen, X., Hagel, J.M. et al. Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy. Nat Chem Biol 15, 384–390 (2019) doi:10.1038/s41589-019-0247-0
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