Genome‐based discovery of pachysiphine synthases in <i>Tabernaemontana elegans</i>

Plant-specialized metabolism represents an inexhaustible source of active molecules, some of which have been used in human health for decades. Among these, monoterpene indole alkaloids (MIAs) include a wide range of valuable compounds with anticancer, antihypertensive, or neuroactive properties. This is particularly the case for the pachysiphine derivatives which show interesting antitumor and anti-Alzheimer activities but accumulate at very low levels in several Tabernaemontana species. Unfortunately, genome data in Tabernaemontanaceae are lacking and knowledge on the biogenesis of pachysiphine-related MIAs in planta remains scarce, limiting the prospects for the biotechnological supply of many pachysiphine-derived biopharmaceuticals. Here, we report a raw version of the toad tree (Tabernaemontana elegans) genome sequence. These new genomic resources led to the identification and characterization of a couple of genes encoding cytochrome P450 with pachysiphine synthase activity. Our phylogenomic and docking analyses highlight the different evolutionary processes that have been recruited to epoxidize the pachysiphine precursor tabersonine at a specific position and in a dedicated orientation, thus enriching our understanding of the diversification and speciation of the MIA metabolism in plants. These gene discoveries also allowed us to engineer the synthesis of MIAs in yeast through the combinatorial association of metabolic enzymes resulting in the tailor-made synthesis of non-natural MIAs. Overall, this work represents a step forward for the future supply of pachysiphine-derived drugs by microbial cell factories.

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Publication Details

Journal
The Plant Journal
Published
2024-10-20
DOI
https://doi.org/10.1111/tpj.17085
Citations
2
Primary Topic
Alkaloids: synthesis and pharmacology
Type
article
Field-Weighted Citation Impact
0.93

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article

Genome‐based discovery of pachysiphine synthases in Tabernaemontana elegans

Ron P. Dirks, Nicolas Gautron, Sébastien Besseau, Michael K. Jensen et al.
2 citations
The Plant Journal
Alkaloids: synthesis and pharmacology
0.93
article

Genome‐based discovery of pachysiphine synthases in Tabernaemontana elegans

Ron P. Dirks, Nicolas Gautron, Sébastien Besseau, Michael K. Jensen, Sarah E. O’Connor, Mehdi A. Beniddir, Chao Sun, Audrey Oudin, Vincent Courdavault, Caroline Birer-Williams, Adriana González Vázquez, Mickaël Durand, Clément Cuello, Hans J. Jansen, Κωνσταντίνος Κουδούνας, Sarah Szwarc, Benoit St‐Pierre, Julien Pétrignet, Enzo Lezin, Thomas Perrot, Florent Magot, Nathalie Giglioli‐Guivarc’h, Pierre Le Pogam, Nicolas Papon
article en
2 citations

Abstract

Plant-specialized metabolism represents an inexhaustible source of active molecules, some of which have been used in human health for decades. Among these, monoterpene indole alkaloids (MIAs) include a wide range of valuable compounds with anticancer, antihypertensive, or neuroactive properties. This is particularly the case for the pachysiphine derivatives which show interesting antitumor and anti-Alzheimer activities but accumulate at very low levels in several Tabernaemontana species. Unfortunately, genome data in Tabernaemontanaceae are lacking and knowledge on the biogenesis of pachysiphine-related MIAs in planta remains scarce, limiting the prospects for the biotechnological supply of many pachysiphine-derived biopharmaceuticals. Here, we report a raw version of the toad tree (Tabernaemontana elegans) genome sequence. These new genomic resources led to the identification and characterization of a couple of genes encoding cytochrome P450 with pachysiphine synthase activity. Our phylogenomic and docking analyses highlight the different evolutionary processes that have been recruited to epoxidize the pachysiphine precursor tabersonine at a specific position and in a dedicated orientation, thus enriching our understanding of the diversification and speciation of the MIA metabolism in plants. These gene discoveries also allowed us to engineer the synthesis of MIAs in yeast through the combinatorial association of metabolic enzymes resulting in the tailor-made synthesis of non-natural MIAs. Overall, this work represents a step forward for the future supply of pachysiphine-derived drugs by microbial cell factories.

The Plant JournalVol. 120(5)
Université de Tours (FR), Centre National de la Recherche Scientifique (FR), Université de Bretagne Occidentale (FR), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Aristotle University of Thessaloniki (GR), Université Paris-Saclay (FR), Novo Nordisk Foundation (DK), Laboratoire de Chémo-biologie synthétique et thérapeutique (FR), Max Planck Institute for Chemical Ecology (DE), Cancer Genomics Centre (NL), Université d'Angers (FR), Technical University of Denmark (DK)
Temple University, Agence Nationale de la Recherche, Conseil Régional du Centre-Val de Loire, Horizon 2020 Framework Programme
Openalex Percentile: Top 24%
Alkaloids: synthesis and pharmacology
0.93
DOIOpen Access PDFOpenAlex
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