TY - JOUR
T1 - A microbial supply chain for production of the anti-cancer drug vinblastine
AU - Zhang, Jie
AU - Hansen, Lea G.
AU - Gudich, Olga
AU - Viehrig, Konrad
AU - Lassen, Lærke M.M.
AU - Schrübbers, Lars
AU - Adhikari, Khem B.
AU - Rubaszka, Paulina
AU - Carrasquer-Alvarez, Elena
AU - Chen, Ling
AU - D’Ambrosio, Vasil
AU - Lehka, Beata
AU - Haidar, Ahmad K.
AU - Nallapareddy, Saranya
AU - Giannakou, Konstantina
AU - Laloux, Marcos
AU - Arsovska, Dushica
AU - Jørgensen, Marcus A.K.
AU - Chan, Leanne Jade G.
AU - Kristensen, Mette
AU - Christensen, Hanne B.
AU - Sudarsan, Suresh
AU - Stander, Emily A.
AU - Baidoo, Edward
AU - Petzold, Christopher J.
AU - Wulff, Tune
AU - O’Connor, Sarah E.
AU - Courdavault, Vincent
AU - Jensen, Michael K.
AU - Keasling, Jay D.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41586-022-05157-3
DO - 10.1038/s41586-022-05157-3
M3 - Journal article
C2 - 36045295
AN - SCOPUS:85137195830
SN - 0028-0836
VL - 609
SP - 341
EP - 347
JO - Nature
JF - Nature
IS - 7926
ER -