Molecular cloning and functional expression of codeinone reductase: the penultimate enzyme in morphine biosynthesis in the opium poppy Papaver somniferum

Plant J. 1999 Jun;18(5):465-75. doi: 10.1046/j.1365-313x.1999.00470.x.


The narcotic analgesic morphine is the major alkaloid of the opium poppy Papaver somniferum. Its biosynthetic precursor codeine is currently the most widely used and effective antitussive agent. Along the morphine biosynthetic pathway in opium poppy, codeinone reductase catalyzes the NADPH-dependent reduction of codeinone to codeine. In this study, we have isolated and characterized four cDNAs encoding codeinone reductase isoforms and have functionally expressed them in Escherichia coli. Heterologously expressed codeinone reductase-calmodulin-binding peptide fusion protein was purified from E. coli using calmodulin affinity column chromatography in a yield of 10 mg enzyme l-1. These four isoforms demonstrated very similar physical properties and substrate specificity. As least six alleles appear to be present in the poppy genome. A comparison of the translations of the nucleotide sequences indicate that the codeinone reductase isoforms are 53% identical to 6'-deoxychalcone synthase from soybean suggesting an evolutionary although not a functional link between enzymes of phenylpropanoid and alkaloid biosynthesis. By sequence comparison, both codeinone reductase and 6'-deoxy- chalcone synthase belong to the aldo/keto reductase family, a group of structurally and functionally related NADPH-dependent oxidoreductases, and thereby possibly arise from primary metabolism.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / biosynthesis
  • Alcohol Oxidoreductases / genetics*
  • Alcohol Oxidoreductases / isolation & purification
  • Alleles
  • Amino Acid Sequence
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • Genes, Plant
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Models, Chemical
  • Molecular Sequence Data
  • Morphine / metabolism*
  • NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases
  • Papaver / genetics*
  • Plants, Medicinal*
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics
  • RNA, Messenger / isolation & purification
  • RNA, Plant / genetics
  • RNA, Plant / isolation & purification
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Substrate Specificity
  • Tissue Distribution


  • DNA, Complementary
  • Isoenzymes
  • RNA, Messenger
  • RNA, Plant
  • Morphine
  • Alcohol Oxidoreductases
  • NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases
  • codeinone reductase (NADPH)

Associated data

  • GENBANK/AF108432
  • GENBANK/AF108433
  • GENBANK/AF108434
  • GENBANK/AF108435
  • GENBANK/AF108436
  • GENBANK/AF108437
  • GENBANK/AF108438