Abstract
AbstractThe Madagascar’s periwinkle is the model plant for studies of plant specialized metabolism and monoterpenoid indole alkaloids (MIAs), and an important source for the anticancer medicine vinblastine. The elucidation of entire 28-step biosynthesis of vinblastine allowed further investigations for the formation of other remarkably complex bioactive MIAs. In this study, we describe the discovery and characterization of vindolinine synthase, a Fe(II)/α-ketoglutarate-dependent (Fe/2OG) dioxygenase, that diverts assembly of tabersonine to vinblastine toward the formation of three alternatively cyclized MIAs: 19S-vindolinine, 19R-vindolinine, and venalstonine. Vindolinine synthase catalyzes a highly unusual, redox-neutral reaction to form a radical from dehydrosecodine, which is further cyclized by hydrolase 2 to form the three MIA isomers. We further show the biosynthesis of vindolinine epimers from tabersonine using hydrolase 2 catalyzed reverse cycloaddition. While the occurrence of vindolinines is rare in nature, the more widely found venalstonine derivatives are likely formed from similar redox-neutral reactions by homologous Fe/2OG dioxygenases.
Funder
Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada
Canada Foundation for Innovation
New Brunswick Innovation Foundation
Fondation de la recherche en santé du Nouveau-Brunswick
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference39 articles.
1. Facchini, P. J. & De Luca, V. Opium poppy and Madagascar periwinkle: model non-model systems to investigate alkaloid biosynthesis in plants. Plant J. 54, 763–784 (2008).
2. O’Connor, S. E. & Maresh, J. J. Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 23, 532–547 (2006).
3. Qu, Y., Safonova, O. & De Luca, V. Completion of the canonical pathway for assembly of anticancer drugs vincristine/vinblastine in Catharanthus roseus. Plant J. 97, 257–266 (2018).
4. Qu, Y. et al. Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast. Proc. Natl Acad. Sci. 112, 6224–6229 (2015).
5. Qu, Y. et al. Geissoschizine synthase controls flux in the formation of monoterpenoid indole alkaloids in a Catharanthus roseus mutant. Planta 25, 1–10 (2017).
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