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

Zhang, Jie; Hansen, Lea G.; Gudich, Olga; Viehrig, Konrad; Lassen, Lærke M. M.; Schrübbers, Lars; Adhikari, Khem B.; Rubaszka, Paulina; Carrasquer-Alvarez, Elena; Chen, Ling; D’Ambrosio, Vasil; Lehka, Beata; Haidar, Ahmad K.; Nallapareddy, Saranya; Giannakou, Konstantina; Laloux, Marcos; Arsovska, Dushica; Jørgensen, Marcus A. K.; Chan, Leanne Jade G.; Kristensen, Mette; Christensen, Hanne B.; Sudarsan, Suresh; Stander, Emily A.; Baidoo, Edward; Petzold, Christopher J.; Wulff, Tune; O’Connor, Sarah E.; Courdavault, Vincent; Jensen, Michael K.; Keasling, Jay D.

doi:10.1038/s41586-022-05157-3

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

Journal Article · Wed Aug 31 00:00:00 EDT 2022 · Nature (London)

DOI:https://doi.org/10.1038/s41586-022-05157-3· OSTI ID:2470808

Zhang, Jie ^[1]; ^[1]; Gudich, Olga ^[1]; ^[1]; Lassen, Lærke M. M. ^[1]; Schrübbers, Lars ^[1]; Adhikari, Khem B. ^[1]; Rubaszka, Paulina ^[1]; ^[1]; ^[1]; D’Ambrosio, Vasil ^[1]; Lehka, Beata ^[1]; Haidar, Ahmad K. ^[1]; Nallapareddy, Saranya ^[1]; Giannakou, Konstantina ^[1]; Laloux, Marcos ^[1]; Arsovska, Dushica ^[1]; Jørgensen, Marcus A. K. ^[1]; Chan, Leanne Jade G. ^[2]; Kristensen, Mette ^[1] more »

Technical University of Denmark, Lyngby (Denmark)
Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
University of Tours (France)
Max Planck Institute for Chemical Ecology, Jena (Germany)
Technical University of Denmark, Lyngby (Denmark); Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); University of California, Berkeley, CA (United States); Chinese Academy of Sciences (CAS), Shenzhen (China). Shenzhen Institute of Advanced Technology

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 vincristine. 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 scale. 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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: European Union (EU); Novo Nordisk Foundation (NNF); USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470808

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7926 Vol. 609; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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