Unveiling the machinery driving atypical cyclisation of monoterpenoid indole alkaloids for metabolic engineering

Our mission

Plants are an inexhaustible source of pharmaceutical compounds, essential component of our pharmacopeia. Unfortunately, these natural products (NP) accumulate in minute amounts in plants while their complex structures render total chemical syntheses highly impractical, leading to the overexploitation of natural resources.

Developing new and complementary approaches to produce highly valuable NPs is thus mandatory to secure supply at midterms while preserving natural resources. This can be notably envisaged through the conversion of abundant and simpler NP precursors that can be extracted from plants commonly grown in Europe.

It’s particularly true for the monoterpenoid indole alkaloids (MIAs), a class of NP used mostly in chemotherapies which are currently produced by semisynthesis resulting in limited supplies at exhorbitant market prices.   MIACYC will focus on the elucidation of an atypical C-N indole cyclization of MIAs found in the biosynthesis of three emblematic MIAs : pleiocarpamine, vincamine and strychnine. These natural products endow with pharmacological properties and occur in three plant models (see below).

 While the enzymatic reactions catalyzing the C-Nindole cyclization are still poorly documented, MIACYC aims identifying the corresponding biosynthetic reactions allowing the development of a new pipeline of pathway elucidation and opening doors for a sustainable production of these compounds and their potential derivatives through yeast metabolic engineering.

                       univ tours                                       bbv                                      
                         paris saclay                                        biocis

Read the articles from our project!

  • The Rauvolfia tetraphylla genome suggests multiple distinct biosynthetic routes for yohimbane monoterpene indole alkaloids in monoterpene indole alkaloid synthesis
    24 novembre 2023 - 1 janvier 2026
    Our results published in Communications Biology, a Portfolio Nature journal, pave the way towards alkaloid bioproduction in yeast, and among them, yohimbine, rauwolscine, corynathine (and their derivatives), therapetuic molecules with selective affinity for α2-adrenergic and α1-adrenergic receptors,
  • Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast
    7 novembre 2023 - 26 août 2025
    Published in Nature Chemical Biology, this collaborative work demonstrates a scalable de novo manufacturing platform for bioactive monoterpenoid indole alkaloids (MIAs, plant metabolites that possess various medicinal properties) in yeast and provides a foundation for further pathway refactoring toward microbial biosynthesis of both native and new-to-nature MIAs.
  • Artificial intelligence for natural product drug discovery
    27 septembre 2023 - 31 mars 2026
    In this review article published in Nature Reviews drug discovery, Dr Mehdi Beniddir from the ANR project, MIACYC and collaborators describe current and future synergies between these developments to effectively identify drug candidates from the plethora of molecules produced by nature.
  • Medicinal plants enter the single-cell multi-omics era
    5 août 2023 - 26 août 2025
    Our new spotlight published in Trends in Plant Science, on a report by Li et al on single-cell multi-omics approach used to elucidate the architecture and regulation of anticancer alkaloid biosynthesis in medicinal plants.
  • Emerging mechanistic insights into the regulation of specialized metabolism in plants
    23 décembre 2022 - 23 décembre 2025
    Published in Nature Plants, this review focuses on translational, transcriptional, epigenetic and chromatin-based regulation and evolution of specialized metabolism genes, a new and forefront research filed. We extrapolate to medicinal plants that synthetize rare molecules and also discuss how this new knowledge could help in improving strategies to produce useful plant-derived pharmaceuticals.
  • Boosting lignan-precursor synthesis in yeast cell factories through co-factor supply optimization
    2 décembre 2022 - 2 décembre 2025
    Through this commentary article, we highlight the outstanding work of the Zhou’s group which recently describes a distinct approach relying on the efficient recycling of enzyme co-factors in yeast to fulfill the synthesis of caffeic acid (CaA) and ferulic acid (FA), two precursors of podophyllotoxin. We discuss how the cofactor recycling approach will undoubtedly pave the way for future high titer production of valuable natural products in yeast.
  • Genome Assembly of the Medicinal Plant Voacanga thouarsii
    29 juillet 2022 - 29 juillet 2025
    In our new article published in Genome Biology and Evolution, we provide the first annotated reference genome of a Voacanga species that, together with the previously published MIA-producing plant genomes, will help understand evolution and diversification of MIA in plants as well as identifying MIA biosynthetic genes to enrich the molecular MIA toolbox used for production of MIA in heterologous hosts.
  • The Vinca minor genome highlights conserved evolutionary traits in monoterpene indole alkaloid synthesis
    18 octobre 2022 - 18 octobre 2025
    The Vinca minor genome finally assembled! Our new publication in G3!The Vinca minor plant synthesizes monoterpene indole alkaloids (MIAs), which are a class of specialized metabolites displaying a wide range of bioactive- and pharmacologically important properties. V. minor mainly accumulates vincamine, which is commercially used as a nootropic. Using a combination of Oxford Nanopore Technologies long read- and Illumina short-read sequencing, a 679,098 Mb V. minor genome was assembled into 296 scaffolds with an N50 scaffold length of 6 Mb, and encoding 29,624 genes.

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Our objectives

The plants we study The plants we study

Identification of new scaffolds

Deciphering the complex metabolism of our 3 plant models would allow us to identify new scaffolds of MIA at the cellular level using metabolomic innovative tools

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Identification of the key enzymes

Acording to metabolomics studies, we'll characterize candidate proteins acting as catalyzers of the expected reactions ie the key enzymes involved in the biosynthesis of C-Nindole  MIAs

Production in microbes of targeted MIA

The functional validation of the candidate genes encoding enzymes involved in C-Nindole alkaloid metabolism and their heterologous expression would allow creating a MIA producting yeast cell factory. 

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