Harnessing the spatial and transcriptional regulation of monoterpenoid indole alkaloid metabolism in Alstonia scholaris leads to the identification of broad geissoschizine cyclase activities

Monoterpene indole alkaloids (MIAs) are valuable metabolites produced in numerous medicinal plants from the Apocynaceae family such as Alstonia scholaris, which synthesizes strictamine, a MIA displaying neuropharmacological properties of a potential importance. To get insights into the MIA metabolism in A. scholaris, we studied here both the spatial and transcriptional regulations of MIA genes by performing a robust transcriptomics analysis of the main plant organs, leaf epidermis but also by sequencing RNA from leaves transiently overexpressing the master transcriptional regulator MYC2. These transcriptomic studies notably demonstrated that the first steps of the MIA pathway are successively distributed in the internal phloem associated parenchyma and epidermis, and that MYC2 exerts a remarkable transcriptional effect by modulating the expression of around 1000 genes. By combining these distinct datasets, we initiated the search for MIA-related genes encoding CYP71, based on the similarity of expression compared to already known MIA genes. Transient expression of these candidates in Nicotiana benthamiana leaves and yeast notably led to the identification of a related isoform of rhazimal synthase (RHS) capable of converting the MIA precursor geissoschizine into akuammicine, strictamine and 16-epi-pleiocarpamine. Investigating its catalytic mechanism revealed that strictamine results from rhazimal deformylation and that a similar mechanism may also explain 16-epi-pleiocarpamine synthesis. This prompted us to rename these enzymes geissoschizine cyclase due to their capacity of cyclizing geissoschizine into three different MIA scaffolds and to form both C-C and C-N bonds. This identification thus illustrates the potential of integrating spatial and transcriptional regulation analysis for MIA gene identification.

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Publication Details

Journal
Plant Physiology and Biochemistry
Published
2024-11-29
DOI
https://doi.org/10.1016/j.plaphy.2024.109363
Citations
8
Primary Topic
Alkaloids: synthesis and pharmacology
Type
article
Field-Weighted Citation Impact
3.73
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article

Harnessing the spatial and transcriptional regulation of monoterpenoid indole alkaloid metabolism in Alstonia scholaris leads to the identification of broad geissoschizine cyclase activities

Arnaud Lanoue, Nicolas Gautron, Sébastien Besseau, Michael K. Jensen et al.
8 citations
Plant Physiology and Biochemistry
Alkaloids: synthesis and pharmacology
3.73
article

Harnessing the spatial and transcriptional regulation of monoterpenoid indole alkaloid metabolism in Alstonia scholaris leads to the identification of broad geissoschizine cyclase activities

Arnaud Lanoue, Nicolas Gautron, Sébastien Besseau, Michael K. Jensen, Mehdi A. Beniddir, Audrey Oudin, Ling Yuan, Duchesse‐Lacours Zamar, Vincent Courdavault, Christelle Dutilleul, Caroline Birer-Williams, Mickaël Durand, Louis‐Valentin Méteignier, Barunava Patra, Bilal Haider Abbasi, Véronique Brunaud, Κωνσταντίνος Κουδούνας, Étienne Delannoy, Sarah Szwarc, Benoit St‐Pierre, Enzo Lezin, Thomas Perrot, Pierre Le Pogam, Nicolas Papon, Chao Sun, Stéphanie Pateyron
article en
8 citations

Abstract

Monoterpene indole alkaloids (MIAs) are valuable metabolites produced in numerous medicinal plants from the Apocynaceae family such as Alstonia scholaris, which synthesizes strictamine, a MIA displaying neuropharmacological properties of a potential importance. To get insights into the MIA metabolism in A. scholaris, we studied here both the spatial and transcriptional regulations of MIA genes by performing a robust transcriptomics analysis of the main plant organs, leaf epidermis but also by sequencing RNA from leaves transiently overexpressing the master transcriptional regulator MYC2. These transcriptomic studies notably demonstrated that the first steps of the MIA pathway are successively distributed in the internal phloem associated parenchyma and epidermis, and that MYC2 exerts a remarkable transcriptional effect by modulating the expression of around 1000 genes. By combining these distinct datasets, we initiated the search for MIA-related genes encoding CYP71, based on the similarity of expression compared to already known MIA genes. Transient expression of these candidates in Nicotiana benthamiana leaves and yeast notably led to the identification of a related isoform of rhazimal synthase (RHS) capable of converting the MIA precursor geissoschizine into akuammicine, strictamine and 16-epi-pleiocarpamine. Investigating its catalytic mechanism revealed that strictamine results from rhazimal deformylation and that a similar mechanism may also explain 16-epi-pleiocarpamine synthesis. This prompted us to rename these enzymes geissoschizine cyclase due to their capacity of cyclizing geissoschizine into three different MIA scaffolds and to form both C-C and C-N bonds. This identification thus illustrates the potential of integrating spatial and transcriptional regulation analysis for MIA gene identification.

Plant Physiology and BiochemistryVol. 219
Université de Tours (FR), Quaid-i-Azam University (PK), Centre National de la Recherche Scientifique (FR), Institut de Chimie des Substances Naturelles (FR), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (FR), University of Kentucky (US), Université de Bretagne Occidentale (FR), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Université Paris Cité (FR), Aristotle University of Thessaloniki (GR), Université Paris-Saclay (FR), Novo Nordisk Foundation (DK), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Institut des Sciences des Plantes de Paris Saclay (FR), Centre Hospitalier Universitaire d'Angers (FR), Services déconcentrés d'appui à la recherche Occitanie-Montpellier (FR), Département Biologie et Amélioration des Plantes (FR), Laboratoire des Biomolécules (FR), Plant Health Institute de Montpellier (FR), Université d'Angers (FR), Technical University of Denmark (DK)
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Alkaloids: synthesis and pharmacology
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