Researchers have engineered the complete biosynthetic pathway for a potential cancer drug into a single yeast strain, paving the way toward the commercial brewing of medically important compounds. Noscapine, a widely used nonnarcotic cough suppressant, can act as a potential cancer drug with purportedly fewer side effects than conventional chemotherapy when administered in high doses. The drug is extracted from opium poppy straws, but poppy farming is time-consuming, prone to environmental vagaries, and can introduce narcotic alkaloids into supply chains. More importantly, noscapine cannot be easily chemically synthesized at commercial scales for medical testing and use. Building on previous work that uncovered a 10-gene cluster underlying noscapine synthesis in opium poppies, Christina D. Smolke and colleagues assembled a biosynthetic pathway composed of 31 bacterial, yeast, plant, and mammalian enzymes, including technically daunting membrane-bound enzymes, into a single strain of brewer's yeast (Saccharomyces cerevisiae). The engineered yeast strain produced 120-230 ng/L noscapine. By optimizing enzyme activity and expression levels, regenerating cofactors to improve enzyme efficiency, and altering fermentation conditions and the composition of the growth medium, the authors boosted production by a factor of 18,000, resulting in 2.2 mg/L noscapine. Though commercial manufacture requires a further 100-fold to 1,000-fold increase in noscapine titers, the findings demonstrate the feasibility of using yeast for the large-scale conversion of simple carbon and nitrogen sources into a medically important plant alkaloid, according to the authors.
###
Article #17-21469: "Complete biosynthesis of noscapine and halogenated alkaloids in yeast," by Yanran Li et al.
MEDIA CONTACT: Christina Smolke, Stanford University, CA; tel: 650-799-6872; e-mail: csmolke@stanford.edu
Journal
Proceedings of the National Academy of Sciences