A modified baker’s yeast (Saccharomyces cerevisiae) has been engineered to produce a precursor compound for two essential cancer medicines. By reconstructing a complex 45-enzyme biosynthetic pathway inside yeast, researchers in China have unlocked the direct microbial synthesis of key precursors for etoposide and teniposide, potentially offering a more efficient way to make the drugs than the current synthetic routes.
Etoposide and teniposide are first-line chemotherapeutics used to treat millions of patients annually for leukaemia, and certain lung and brain tumours. Despite their critical importance, their production relies on extraction of a precursor, podophyllotoxin, from an endangered Himalayan plant that takes four to five years to accumulate sufficient quantities of the compound. The subsequent syntheses require more than 10 steps, precious metal catalysts, and give yields below 20%.
Now, researchers led by Yating Hu and Luqi Huang at Capital Medical University in Beijing have reconstructed the complete biosynthetic pathway in baker’s yeast. To do this, they made over 60 genetic edits and inserted 45 heterologous genes – sourced from plants, bacteriaand fungi – into the yeast genome.
The engineered yeast produces the immediate precursor to etoposide from glucose in a simple three-day fermentation process. By shifting the most stereochemically challenging step into a biological host, the team eliminated the need for tedious sugar-protection steps, hazardous reagents, and expensive catalysts. Once the precursor molecule is isolated from the yeast, a final acetalisation step yields etoposide at an impressive 89% yield, or teniposide at 65%.
‘Excellent enzyme discovery, excellent pathway engineering, and a genuinely clever decision about where the hard chemistry ought to be done,’ says Jay Keasling, a bioengineer at University of California, Berkeley who was not involved in the study. ‘The podophyllotoxin pathway is among the least forgiving targets left in plant natural-product biosynthesis.’ He explains that a key aspect of the process is the use of an enzyme called UGT709AX1, which cleanly executes a tricky glycosylation step that ‘makes current semi-synthesis so miserable.’
However, Keasling notes that while the single-step chemical conversion scales ‘without drama,’ the underlying biology is not yet ready for commercial production. This is because the precursor compound is produced in concentrations around four orders of magnitude below the grams-per-liter needed for industrial fermentation. Still, he remains optimistic, emphasising that the study successfully converts a complex biological unknown into a clear engineering challenge that can now be systematically solved over time.
