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Synthetic Biology

Engineered brewer’s yeast make potential cancer drug

Process eases production of noscapine, naturally made by opium poppies, and analogs

by Stu Borman
April 5, 2018 | A version of this story appeared in Volume 96, Issue 15

Chemical line structure of noscapine.

Researchers have engineered into yeast an unusually complex biosynthetic pathway leading to the potential cancer drug noscapine and a noscapine precursor that can be used to make drug analogs.

Noscapine has been used as a cough medicine since the 1960s. Preclinical trials suggest it also kills cancer with relatively mild side effects. But it is obtained from poppy plants, which have to be protected because they also produce controlled substances like morphine. Chemical syntheses of noscapine require too many steps to be practical commercially.

To provide a better source, Christina D. Smolke of Stanford University and coworkers engineered yeast with a noscapine pathway that includes 25 plant, bacteria, and mammalian genes and six modified yeast genes (Proc. Natl. Acad. Sci. USA 2018, DOI: 10.1073/pnas.1721469115). Seven of the genes are for enzymes that must enter yeast endoplasmic reticulum membranes to fold and work properly, making them particularly challenging to engineer.

Commercializing the yeast process would require a two to three order-of-magnitude boost in noscapine output, but the researchers believe they can improve output 100-fold just by moving the system from lab flasks to large-scale bioreactors.

The yeast normally feed on glucose, but feeding them tyrosine derivatives instead yielded derivatives of reticuline, a noscapine precursor. Jens Nielsen of Chalmers University of Technology says that the reticuline capability opens opportunities for “many new compounds that may have interesting pharma applications.”

Stanford has patented the yeast, and Antheia, a company Smolke cofounded, has licensed the technology.


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