CYP719B1 is salutaridine synthase, the C-C phenol-coupling enzyme of morphine biosynthesis in opium poppy

J Biol Chem. 2009 Sep 4;284(36):24432-42. doi: 10.1074/jbc.M109.033373. Epub 2009 Jun 30.

Abstract

Morphine is a powerful analgesic natural product produced by the opium poppy Papaver somniferum. Although formal syntheses of this alkaloid have been reported, the morphine molecule contains five stereocenters and a C-C phenol linkage that to date render a total synthesis of morphine commercially unfeasible. The C-C phenol-coupling reaction along the biosynthetic pathway to morphine in opium poppy is catalyzed by the cytochrome P450-dependent oxygenase salutaridine synthase. We report herein on the identification of salutaridine synthase as a member of the CYP719 family of cytochromes P450 during a screen of recombinant cytochromes P450 of opium poppy functionally expressed in Spodoptera frugiperda Sf9 cells. Recombinant CYP719B1 is a highly stereo- and regioselective enzyme; of forty-one compounds tested as potential substrates, only (R)-reticuline and (R)-norreticuline resulted in formation of a product (salutaridine and norsalutaridine, respectively). To date, CYP719s have been characterized catalyzing only the formation of a methylenedioxy bridge in berberine biosynthesis (canadine synthase, CYP719A1) and in benzo[c]phenanthridine biosynthesis (stylopine synthase, CYP719A14). Previously identified phenol-coupling enzymes of plant alkaloid biosynthesis belong only to the CYP80 family of cytochromes. CYP719B1 therefore is the prototype for a new family of plant cytochromes P450 that catalyze formation of a phenol-couple.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Catalysis
  • Cell Line
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Gene Expression
  • Molecular Sequence Data
  • Morphinans / chemistry*
  • Morphinans / metabolism
  • Morphine / biosynthesis*
  • Morphine / chemistry
  • Papaver / enzymology*
  • Papaver / genetics
  • Plant Proteins / chemistry*
  • Plant Proteins / genetics
  • Plant Proteins / metabolism
  • Recombinant Proteins
  • Spodoptera

Substances

  • Morphinans
  • Plant Proteins
  • Recombinant Proteins
  • Morphine
  • salutaridine
  • Cytochrome P-450 Enzyme System

Associated data

  • GENBANK/EF451150