A microbial supply chain for production of the anti-cancer drug vinblastine

Jie Zhang, Lea G. Hansen, Olga Gudich, Konrad Viehrig, Lærke M. M. Lassen, Lars Schrübbers, Khem B. Adhikari, Paulina Rubaszka, Elena Carrasquer-Alvarez, Ling Chen, Vasil D’Ambrosio, Beata Lehka, Ahmad K. Haidar, Saranya Nallapareddy, Konstantina Giannakou, Marcos Laloux, Dushica Arsovska, Marcus A. K. Jørgensen, Leanne Jade G. Chan, Mette Kristensen, Hanne B. Christensen, Suresh Sudarsan, Emily A. Stander, Edward Baidoo, Christopher J. Petzold, Tune Wulff, Sarah E. O’Connor, Vincent Courdavault, Michael K. Jensen () and Jay D. Keasling ()
Additional contact information
Jie Zhang: Technical University of Denmark
Lea G. Hansen: Technical University of Denmark
Olga Gudich: Technical University of Denmark
Konrad Viehrig: Technical University of Denmark
Lærke M. M. Lassen: Technical University of Denmark
Lars Schrübbers: Technical University of Denmark
Khem B. Adhikari: Technical University of Denmark
Paulina Rubaszka: Technical University of Denmark
Elena Carrasquer-Alvarez: Technical University of Denmark
Ling Chen: Technical University of Denmark
Vasil D’Ambrosio: Technical University of Denmark
Beata Lehka: Technical University of Denmark
Ahmad K. Haidar: Technical University of Denmark
Saranya Nallapareddy: Technical University of Denmark
Konstantina Giannakou: Technical University of Denmark
Marcos Laloux: Technical University of Denmark
Dushica Arsovska: Technical University of Denmark
Marcus A. K. Jørgensen: Technical University of Denmark
Leanne Jade G. Chan: Joint BioEnergy Institute
Mette Kristensen: Technical University of Denmark
Hanne B. Christensen: Technical University of Denmark
Suresh Sudarsan: Technical University of Denmark
Emily A. Stander: University of Tours
Edward Baidoo: Joint BioEnergy Institute
Christopher J. Petzold: Joint BioEnergy Institute
Tune Wulff: Technical University of Denmark
Sarah E. O’Connor: Max Planck Institute for Chemical Ecology
Vincent Courdavault: University of Tours
Michael K. Jensen: Technical University of Denmark
Jay D. Keasling: Technical University of Denmark

Nature, 2022, vol. 609, issue 7926, 341-347

Abstract: Abstract Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine1. As MIAs are difficult to chemically synthesize, the world’s supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale2,3. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.

Date: 2022
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DOI: 10.1038/s41586-022-05157-3

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