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Drug breweries of the future

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Genetically modified yeasts could soon provide a source of opiates and other drugs previously only obtainable from plants.

The advantages of cheaper and more controllable production techniques will have to be considered against the risks of the technology being used for illegal drug manufacturing, however. Modified yeast strains could soon make it possible for anyone to produce drugs like heroin using little more than a homebrew kit.

A number of drugs (like antimalarial artemisinin, for example), scents and flavours once only obtainable from plants can already be made using genetically engineered organisms. Opiates are an obvious target to add to this list because the source crop must be grown in highly regulated conditions and the chemicals are difficult and expensive to make in a laboratory.

Recently published work in Nature Chemical Biology used the yeast Saccharomyces cerevisiae to convert glucose into (S)-reticuline — a key intermediate in the synthesis of benzylisoquinoline alkaloids (BIAs), which include the opiates. Combining this part of the pathway with work carried out elsewhere on other stages could enable opiates to be produced from glucose in two or three years’ time.

This recent achievement had previously been hindered by a single step in the process by which poppies convert tyrosine into l-dopa, which uses an enzyme that has not been identified. While enzymes from other plants also carry out this reaction, they immediately convert the l-dopa into dopaquinone, an unwanted by-product.

To solve this problem, bioengineers inserted a sugar beet enzyme that converts tyrosine into l-dopa into S cerevisiae cells, and induced mutations in the cells to produce multiple variants of the enzyme. After screening nearly half a million mutants they found an enzyme that produced much more l-dopa relative to dopaquinone.

Other teams are working on producing tropane alkaloids such as cocaine but this is further away, as critical steps in the coca plants’ production pathway are not understood. Yet once processes like this are clarified, yeast could theoretically be engineered to make any substance that plants produce.

In order to hinder potential illegal use of this technology, an article in Nature suggests how yeast strains could be made less appealing to criminals. For example, they could be engineered to make only opiates with limited street value, such as thebaine. Weaker strains could make it harder to produce opiates outside of laboratory settings, and yeasts could be engineered with unusual nutrient dependencies, or even a DNA ‘watermark’ to make them more readily identifiable.

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From: Beyond pharmacy blog

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