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Natural Products

Periwinkle gives up its cancer-busting secrets

Key enzymes in complex biosynthesis could enable alkaloid production

by Mark Peplow, special to C&EN
May 6, 2018 | APPEARED IN VOLUME 96, ISSUE 19

09619-scicon10-periwinklecxd.jpg
Credit: Andrew Davis/John Innes Centre
The Madagascar periwinkle is the primary source of anticancer agents vinblastine and vincristine.

The humble Madagascar periwinkle (Catharanthus roseus) produces two potent alkaloids, vinblastine and vincristine, which are used to treat various cancers. The little plant’s mighty biosynthetic feat involves more than 30 chemical steps. Now, researchers have provided the first complete picture of the alkaloids’ synthesis (Science 2018, DOI: 10.1126/science.aat4100). A decades-long mystery centered on how the periwinkle transforms stemmadenine acetate into tabersonine and catharanthine, which ultimately couple to make the cancer-fighting compounds. Vincent Courdavault at the University of Tours and Sarah E. O’Connor at the John Innes Centre used gene-silencing experiments to show that the periwinkle lost its ability to make tabersonine and catharanthine without four crucial enzymes: precondylocarpine acetate synthase (PAS), dihydroprecondylocarpine synthase, tabersonine synthase, and catharanthine synthase. In principle, these enzymes could be expressed in a bacterium or yeast to help produce the anticancer alkaloids in a fermentation process; today’s supplies are sourced exclusively from the periwinkle itself. Indeed, the team has already modified Escherichia coli to make three of the enzymes, but PAS has proved much less cooperative: “One of the first challenges is to work out how to express PAS in a convenient host,” O’Connor says.

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