Dataset Information

A microbial supply chain for production of 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 extractions of precursors vindoline and catharanthine from the plant Catharanthus roseus, followed by chemical coupling and reduction to form vinblastine. Here, we demonstrate de novo microbial biosynthesis of vindoline and catharanthine from renewable feedstocks such as simple sugar and amino acids using highly engineered yeast. The study showcases the longest biosynthetic pathway refactored into a microbial cell factory to date, including 29 enzymatic steps from the yeast native metabolite geranyl pyrophosphate to catharanthine and vindoline. We made 44 genetic edits to yeast that include expression of 35 heterologous genes from plants as well as deletions, knock-downs, and overexpression of 10 yeast genes or variants thereof to improve the precursor supply. Finally, we demonstrate one-step in vitro vinblastine production using chemical coupling and reduction of vindoline and catharanthine. Not only is the yeast a scalable platform for production of vinblastine, it is also a platform for production of more than 2,000 different natural and new-to-nature MIAs.

ORGANISM(S): Saccharomyces Cerevisiae

SUBMITTER: Chris Petzold

PROVIDER: PXD024976 | panorama | Fri Sep 09 00:00:00 BST 2022

REPOSITORIES: PanoramaPublic

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

Zhang Jie J Hansen Lea G LG Gudich Olga O Viehrig Konrad K Lassen Lærke M M LMM Schrübbers Lars L Adhikari Khem B KB Rubaszka Paulina P Carrasquer-Alvarez Elena E Chen Ling L D'Ambrosio Vasil V Lehka Beata B Haidar Ahmad K AK Nallapareddy Saranya S Giannakou Konstantina K Laloux Marcos M Arsovska Dushica D Jørgensen Marcus A K MAK Chan Leanne Jade G LJG Kristensen Mette M Christensen Hanne B HB Sudarsan Suresh S Stander Emily A EA Baidoo Edward E Petzold Christopher J CJ Wulff Tune T O'Connor Sarah E SE Courdavault Vincent V Jensen Michael K MK Keasling Jay D JD

Nature 20220831 7926

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<sup>1</sup>. 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 ...[more]

PMID: 36045295

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Project description:The human gut microbiota is a complex microbial community with critical functions for the host, including the transformation of various chemicals. While effects on microorganisms has been evaluated using single-species models, their functional effects within more complex microbial communities remain unclear. In this study, we investigated the response of a simplified human gut microbiota model (SIHUMIx) cultivated in an in vitro bioreactor system in combination with 96 deep-well plates after exposure to 90 different xenobiotics, comprising 54 plant protection products and 36 food additives and dyes, at environmentally relevant concentrations. We employed metaproteomics and metabolomics to evaluate changes in bacterial abundances, the production of Short Chain Fatty Acids (SCFAs), and the regulation of metabolic pathways. Our findings unveiled significant changes induced by 23 out of 54 plant protection products and 28 out of 36 food additives across all three categories assessed. Notable highlights include azoxystrobin, fluoroxypyr, and ethoxyquin causing a substantial reduction (log2FC <-0.5) in the concentrations of the primary SCFAs: acetate, butyrate, and propionate. Several food additives had significant effects on the relative abundances of bacterial species; for example, acid orange 7 and saccharin led to a 75% decrease in Clostridium butyricum, with saccharin causing an additional 2.5-fold increase in E. coli compared to the control. Furthermore, both groups exhibited up- and down-regulation of various pathways, including those related to the metabolism of amino acids such as histidine, valine, leucine, and isoleucine, as well as bacterial secretion systems and energy pathways like starch, sucrose, butanoate, and pyruvate metabolism. This research introduces an efficient in vitro technique that enables high-throughput screening of the structure and function of a simplified and well-defined human gut microbiota model against 90 chemicals using metaproteomics and metabolomics. We believe this approach will be instrumental in characterizing chemical-microbiota interactions especially important for regulatory chemical risk assessments.

Dataset Information

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

Publications

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

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