Yeast makes chemo

As far as they can determine, this is the most complex biosynthetic pathway ever transferred to a micro-organism. It comprises 31 steps in total. According to Keasling, it demonstrates that you can get yeast cells to produce virtually any natural substance — cells that have the considerable advantage of being able to operate effortlessly on an industrial scale.

Rosy periwinkle

Vinblastine inhibits cell division. The substance has been used against various forms of cancer for half a century, including Hodgkin’s disease. It is unpleasant stuff, but there is still nothing better. It is extracted from the leaves of the rosy periwinkle, Catharanthus roseus, (see main photograph) an ornamental plant originally native to Madagascar. Yet at least 500 kilograms of leaves are needed to produce a single gram of the chemotherapy drug, and there has already been one prolonged shortage in recent years. In the laboratory, vinblastine can now be chemically synthesised, but the numerous stereocentres make the synthesis a laborious procedure that is difficult to scale up.

A few years ago, the enzymes that C. roseus uses to produce it were identified, and Keasling has now put that knowledge to use. He assembled the genetic codes of 34 of those enzymes into yeast cells, with 22 other modifications required to ensure that everything was correctly expressed.

Intermediates

The effort has succeeded to the extent that the yeast cells now correctly produce the intermediates vindoline and catharanthine. Only the final enzyme, which must assemble those two into vinblastine, is still not functioning properly. This is not a problem, however; to boost the yield from leaves, vindoline and catharanthine are already extracted from them and subsequently joined together in vitro.

The research was carried out at DTU Biosustain, in full the Novo Nordisk Foundation Center for Biosustainability in Lyngby, Denmark. Keasling, who is most commonly associated with Berkeley in California, serves as its scientific director.

J. Zhang, et al, ‘A microbial supply chain for the production of the anti-cancer drug vinblastine’, Nature (2022) Open Access