An engineered yeast that can complete the early steps of opioid synthesis, producing (S)-reticuline from glucose, is reported in a paper published online this week in Nature Chemical Biology. Previous studies have shown that engineered yeasts can complete the final steps of opioid synthesis. Future research to refine and bridge these pathways may eventually allow for large-scale, low cost production of opioids.
Many, widely-used drugs are isolated or manufactured from plant extracts because their structural complexity precludes their cost-effective synthesis in the laboratory. Systems using engineered microbes, such as yeasts, to produce these compounds are recently becoming a reality thanks to advances in DNA sequencing and synthetic biology. Benzylisoquinoline alkaloids (BIAs) are a large family of plant-derived chemicals that include the compounds morphine and codeine. They have been difficult to produce using microbes because a key enzyme early in the pathway that can work in yeast to convert L-tyrosine to L-DOPA (a precursor to dopamine), has not been found.
To address this, John Dueber and colleagues developed a unique colour-coded biosensor which allowed them to identify the missing enzyme, which they then mutated to make it more productive. They genetically engineered the yeast Saccharomyces cerevisiae to produce this enzyme, allowing the first demonstration of the conversion of glucose to dopamine by yeast. The authors then modified the yeast further, adding DNA from other species, so that it could perform subsequent reactions in the pathway, eventually producing the intermediary, (S)-reticuline. One more step is now required to bridge the two pathways.
Pamela Peralta-Yahya states in an accompanying News & Views that "Given that downstream BIA pathway enzymes have already been shown to express in yeast, this work opens the door to the production of complex BIAs directly from glucose."
Comment: Regulate 'home-brew' opiates
The synthesis of opiates by genetically engineered yeast requires fast and flexible regulation to protect the public and the research community, say Kenneth Oye and colleagues in a Comment published by Nature this week.
The paper published in Nature Chemical Biology this week, and one published by PloS ONE in April, describe steps of an engineered yeast pathway that could make morphine from sugar. The research could lead to cheaper, less addictive and more effective analgesics, say Oye and co–authors. They warn, however, that this development could dramatically increase illicit access to opiates, by generating a drug source that easy to grow, conceal and distribute.
In principle, anyone "would be able to grow the yeast using a home-brew kit for beer-making", they say, adding that users would probably need to drink only 1–2 millilitres of 'opiate homebrew' to obtain a standard prescribed dose of morphine.
The authors urge the synthetic biology community, in tandem with regulators, to act fast. Their recommendations include: establishing policies to keep engineered yeast strains within licensed facilities and in the hands of authorized researchers and technicians; reducing the attractiveness of engineered yeast strains in the illicit marketplace (by engineering strains with unusual nutrient needs, for instance); and implementing a flexible and responsive regulatory approach.
The researchers working on opiate production in yeast told the Nature Comment authors about their feats several months ago, long before moving on to develop and commercialize their tools. "With all the signs that synthetic biology is coming of age, this type of responsible conduct is imperative," Oye and co-authors conclude.