Yeast Programmed For Opioid Total Synthesis

Biotechnology: Researchers stitched together complete pathway from glucose to morphine

Celia Henry Arnaud

This was a milestone year for researchers who have been engineering yeast to make morphine and related alkaloids. The enzymes needed to connect previously known pieces of the biosynthetic pathway were finally identified. First, teams led by Vincent J. J. Martin of Concordia University and by John E. Dueber of the University of California, Berkeley, reported the front and back halves of the biosynthetic pathway. Martin’s team engineered yeast to produce codeine—morphine’s immediate precursor—starting from (R)-reticuline, an intermediate in the pathway (PLOS One 2015, DOI: 10.1371/journal.pone.0124459). Martin’s and Dueber’s teams then collaborated to engineer yeast that convert glucose via a multistep process into (S)-reticuline—(R)-reticuline’s precursor (Nat. Chem. Biol. 2015, DOI: 10.1038/nchembio.1816). To achieve that conversion, they needed to find an enzyme that efficiently transforms tyrosine to L-DOPA on the way from glucose to (S)-reticuline. That left the conversion of (S)-reticuline to (R)-reticuline as the only missing step. Multiple groups reported that final piece later in the year. Ian A. Graham and coworkers at the University of York identified the enzyme that poppies use to convert (S)-reticuline to (R)-reticuline. The enzyme has two modules: a cytochrome P450 that oxidizes (S)-reticuline to 1,2-dehydroreticuline and an oxidoreductase that completes the conversion to (R)-reticuline (Science 2015, DOI: 10.1126/science.aab1852). In August, Christina D. Smolke and coworkers at Stanford University reported the complete biosynthesis of opioids in yeast, including independently finding a fusion protein that converts (S)-reticuline to (R)-reticuline (Science 2015, DOI: 10.1126/science.aac9373). Smolke’s team stitched the entire pathway together with more than 20 enzymes from plants, mammals, bacteria, and yeast. The completion of the pathway has raised concerns about the potential for “home brew” opiates and led some policy experts to call for increased oversight and security measures. But bioengineers note that much work is still needed before any opiate production with yeast will be efficient.

Researchers found the final piece of the biosynthetic pathway to make morphine and other opioids starting from glucose. A fusion protein with two modules catalyzes the missing transformation of (S)-reticuline to (R)-reticuline.

Researchers found the final piece of the biosynthetic pathway to make morphine and other opioids starting from glucose. A fusion protein with two modules catalyzes the missing transformation of (S)-reticuline to (R)-reticuline.

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