Scientists have completed key steps needed to turn sugar-fed yeast into a microbial factory for producing morphine and potentially other drugs, including antibiotics and anti-cancer therapeutics.
Over the past decade, a handful of synthetic-biology labs have been working on replicating in microbes a complex, 15-step chemical pathway in the poppy plant to enable production of therapeutic drugs.
Researchers have independently recreated different sections of the poppy's drug pathway using E coli or yeast, but what had been missing until now were the final steps that would allow a single organism to perform the task from start to finish.
University of California, Berkeley bioengineer John Dueber teamed up with microbiologist Vincent Martin at Concordia University in Montreal, to overcome that hurdle by replicating the early steps in the pathway in an engineered strain of yeast.
They were able to synthesise reticuline, a compound in poppy, from tyrosine, a derivative of glucose.
"What you really want to do from a fermentation perspective is to be able to feed the yeast glucose, which is a cheap sugar source, and have the yeast do all the chemical steps required downstream to make your target therapeutic drug," said Dueber, the study's principal investigator.
"With our study, all the steps have been described, and it's now a matter of linking them together and scaling up the process. It's not a trivial challenge, but it's doable," said Dueber.
Benzylisoquinoline alkaloids, or BIAs, are the class of highly bioactive compounds found in the poppy, and that family includes some 2,500 molecules isolated from plants.
Perhaps the best-known trail in the BIA pathway is the one that leads to the opiates, such as codeine, morphine and thebaine, a precursor to oxycodone and hydrocodone. All are controlled substances.
But different trails will lead to the antispasmodic papaverine or to the antibiotic precursor dihydrosanguinarine.
The researchers found that by repurposing an enzyme from beets that is naturally used in the production of their vibrant pigments, they could coax yeast to convert tyrosine, an amino acid readily derived from glucose, into dopamine.
The researchers were able to reconstitute the full seven-enzyme pathway from tyrosine to reticuline in yeast.
"Getting to reticuline is critical because from there, the molecular steps that produce codeine and morphine from reticuline have already been described in yeast," said Martin.
The study was published in the journal Nature Chemical Biology.
