RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy

Nat Biotechnol. 2004 Dec;22(12):1559-66. doi: 10.1038/nbt1033. Epub 2004 Nov 14.


We report on the silencing of codeinone reductase (COR) in the opium poppy, Papaver somniferum, using a chimeric hairpin RNA construct designed to silence all members of the multigene COR family through RNA interference (RNAi). After gene silencing, the precursor alkaloid (S)-reticuline-seven enzymatic steps upstream of codeinone-accumulated in transgenic plants at the expense of morphine, codeine, oripavine and thebaine. Methylated derivatives of reticuline also accumulated. Analysis verified loss of Cor gene transcript, appearance of 22-mer degradation products and reduction of enzyme activity. The surprising accumulation of (S)-reticuline suggests a feedback mechanism preventing intermediates from general benzylisoquinoline synthesis entering the morphine-specific branch. However transcript levels for seven other enzymes in the pathway, both before and after (S)-reticuline, were unaffected. This is the first report of gene silencing in transgenic opium poppy and of metabolic engineering to cause the high-yield accumulation of the nonnarcotic alkaloid reticuline.

MeSH terms

  • Alcohol Oxidoreductases / deficiency*
  • Alcohol Oxidoreductases / genetics
  • Alkaloids / genetics
  • Alkaloids / metabolism*
  • Benzylisoquinolines / metabolism*
  • Cells, Cultured
  • Genetic Engineering / methods*
  • Morphine / metabolism*
  • NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases
  • Papaver / genetics*
  • Papaver / metabolism*
  • Plants, Genetically Modified / genetics
  • Plants, Genetically Modified / metabolism*
  • RNA Interference*


  • Alkaloids
  • Benzylisoquinolines
  • Morphine
  • Alcohol Oxidoreductases
  • NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases
  • codeinone reductase (NADPH)
  • reticuline