» Articles » PMID: 36045295

A Microbial Supply Chain for Production of the Anti-cancer Drug Vinblastine

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 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.

Citing Articles

Modeling for understanding and engineering metabolism.

Nielsen J, Petranovic D QRB Discov. 2025; 6:e11.

PMID: 40070847 PMC: 11894412. DOI: 10.1017/qrd.2025.1.


Protein recognition methods for diagnostics and therapy.

Montoya R, Deckerman P, Guler M BBA Adv. 2025; 7:100149.

PMID: 40060358 PMC: 11889627. DOI: 10.1016/j.bbadva.2025.100149.


Systematic biotechnological production of isoprenoid analogs with bespoke carbon skeletons.

Wang L, Rosenfeldt M, Koutsaviti A, Harizani M, Zhao Y, Leelahakorn N Nat Commun. 2025; 16(1):2098.

PMID: 40025103 PMC: 11873216. DOI: 10.1038/s41467-025-57494-2.


Creation of a eukaryotic multiplexed site-specific inversion system and its application for metabolic engineering.

Li J, Gong S, Ma Y, Han P, Wang N, Fu Z Nat Commun. 2025; 16(1):1918.

PMID: 39994248 PMC: 11850598. DOI: 10.1038/s41467-025-57206-w.


A concise enzyme cascade enables the manufacture of natural and halogenated protoberberine alkaloids.

Li F, Yuan Z, Gao Y, Deng Z, Zhang Y, Luo Z Nat Commun. 2025; 16(1):1904.

PMID: 39988594 PMC: 11847921. DOI: 10.1038/s41467-025-57280-0.


References
1.
Ishikawa H, Colby D, Seto S, Va P, Tam A, Kakei H . Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues. J Am Chem Soc. 2009; 131(13):4904-16. PMC: 2727944. DOI: 10.1021/ja809842b. View

2.
Jeong W, Lim H . A UPLC-ESI-Q-TOF method for rapid and reliable identification and quantification of major indole alkaloids in Catharanthus roseus. J Chromatogr B Analyt Technol Biomed Life Sci. 2018; 1080:27-36. DOI: 10.1016/j.jchromb.2018.02.018. View

3.
Brown S, Clastre M, Courdavault V, OConnor S . De novo production of the plant-derived alkaloid strictosidine in yeast. Proc Natl Acad Sci U S A. 2015; 112(11):3205-10. PMC: 4371906. DOI: 10.1073/pnas.1423555112. View

4.
OConnor S, Maresh J . Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat Prod Rep. 2006; 23(4):532-47. DOI: 10.1039/b512615k. View

5.
Prasad V, Mailankody S . Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval. JAMA Intern Med. 2017; 177(11):1569-1575. PMC: 5710275. DOI: 10.1001/jamainternmed.2017.3601. View