Key Enzyme Poppies Use To Synthesize Morphine Identified

For years, researchers have been unable to identify an enzyme that the opium poppy Papaver somniferum uses to synthesize morphine. Without the enzyme, which sits in the middle of the plant’s biosynthetic pathway and converts the intermediate (S)-reticuline into (R)-reticuline, poppies can’t make morphine or related opioid compounds, known collectively as morphinans.

Now a team led by Ian A. Graham of the University of York, in England, has finally identified that protein, which they call STORR, for (S)-to-(R)-reticuline (Science 2015, DOI: 10.1126/science.aab1852). STORR turns out to be a fusion of two enzyme modules. The first module, a cytochrome P450, oxidizes (S)-reticuline to form 1,2-dehydroreticuline. The other module, an oxido­reductase, converts that product into (R)-reticuline.

The new protein brings the idea of bioengineered morphine closer to reality. Identifying the STORR protein makes microbial production of morphine feasible, says Hiromichi Minami, a bacterial engineer at Ishikawa Prefectural University, in Japan, who was not involved in the study.

To find the missing enzyme, Graham’s team identified mutant poppy plants that accumulate (S)-reticuline instead of making morphinans. The researchers guessed that these plants probably had faulty versions of the enzyme they were looking for.

Ultimately, they fished the gene for the unknown enzyme out of a library of genes expressed in poppies. To do so, they used as bait a short fragment of RNA that interferes with another enzyme in the morphine pathway with a similar sequence. They then sequenced the same gene from three mutants and found it to be disrupted.

As a plant scientist, Graham plans to use the information about the discovered fusion protein to help pharmaceutical firm GlaxoSmithKline improve poppy plants grown commercially for various alkaloids.

“This was the last remaining step to be described for synthesis of morphinans,” says Vincent J. J. Martin, a synthetic biology researcher at Concordia University, in Montreal, who has been working on engineering yeast to make various alkaloids. “Now the story is complete.”