Pharmaceutical factory in yeast

Genetic engineers forced yeast to synthesize a cure for cough and cancer

Daria Spasskaya, N+1

Bioengineers have collected in baker's yeast a complete pathway for the synthesis of a plant alkaloid – noscapine, which is known as a cough medicine, but also has an anti-cancer effect, according to an article in the Proceedings of the National Academy of Sciences (Li et al., Complete biosynthesis of noscapine and halogenated alkaloids in yeast). Perhaps in the near future, the alkaloid can be obtained using microbial biotechnology, instead of isolating it from opium poppy.

Noscapine– an alkaloid of opium poppy, has been used in the world as a cough medicine for more than 50 years. Unlike other substances contained in poppy, it does not have analgesic and narcotic effects, but in several studies it has demonstrated the property of suppressing the growth of cancer cells. Currently, noscapine and its derivatives (noscapinoids) are considered as potential antitumor agents, and in some countries it is even "illegally" used as a cure for cancer.

Noscapine is traditionally obtained from plant raw materials, however, compared to opioids, its production is unprofitable, and the chemical synthesis pathway is too expensive to obtain large batches of the product. In 2012, a cluster of 10 genes necessary for the synthesis of noscapine was identified in the maca genome, and since then bioengineers have been trying to establish a microbial production method and adapt the baker's yeast Saccharomyces cerevisiae for the synthesis of the substance.

Researchers from Stanford University, led by Christina Smolke, were previously able to reproduce the synthesis pathway of noscapine in yeast from its predecessors. In the new work, scientists combined enzymes in one strain for the step–by-step biosynthesis of key points of substance production - (S)-reticulin from glucose, then (S)-canadine from (S)-reticulin, and finally, noscapine from (S)-canadine. Thus, the final strain is able to produce noscapine from a universal raw material – glucose.

In order to reproduce the synthesis pathway, the authors embedded 25 heterologous genes from other organisms – bacteria, plants and mammals - into the yeast genome, and also increased the expression of six of their own yeast genes. The strains obtained in the first experiments synthesized noscapine in very small quantities, about a hundred nanograms per liter. However, further optimization of gene expression and fermentation conditions led to an increase in productivity by 18 thousand times, and the final strain already produced several milligrams of the substance per liter of growth medium. Nevertheless, for industrial production, the productivity of yeast will need to be increased at least a hundred times more, as well as reduce the concentrations of synthesis by-products.

Scientists emphasize that their work opens up the possibility of synthesizing many complex plant alkaloids using microbial bioengineering. This approach will make it possible not to depend on plant raw materials and to obtain the necessary substances under standard conditions at the plant.

Previously, Smolke's research group collected in baker's yeast a complete pathway for the synthesis of two opioids from glucose: the precursor of morphine, thebaine, and the narcotic analgesic hydrocodone.

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