A Catharanthus roseus Fe(II)/α-ketoglutarate-dependent dioxygenase catalyzes a redox-neutral reaction responsible for vindolinine biosynthesis
Language English Country Great Britain, England Media electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
35680936
PubMed Central
PMC9184523
DOI
10.1038/s41467-022-31100-1
PII: 10.1038/s41467-022-31100-1
Knihovny.cz E-resources
- MeSH
- Catharanthus * metabolism MeSH
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO metabolism MeSH
- Hydrolases metabolism MeSH
- Oxidation-Reduction MeSH
- Gene Expression Regulation, Plant MeSH
- Plant Proteins genetics MeSH
- Secologanin Tryptamine Alkaloids * metabolism MeSH
- Vinblastine analogs & derivatives metabolism MeSH
- Ferrous Compounds metabolism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO MeSH
- Hydrolases MeSH
- Plant Proteins MeSH
- Secologanin Tryptamine Alkaloids * MeSH
- Vinblastine MeSH
- vindolinine MeSH Browser
- Ferrous Compounds MeSH
The 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.
Department of Biological Sciences Brock University St Catharines ON Canada
Department of Chemical Engineering University of New Brunswick Fredericton NB Canada
Department of Chemistry Charles University Prague Praha Czech Republic
Department of Chemistry University of New Brunswick Fredericton NB Canada
See more in PubMed
Facchini PJ, De Luca V. Opium poppy and Madagascar periwinkle: model non-model systems to investigate alkaloid biosynthesis in plants. Plant J. 2008;54:763–784. doi: 10.1111/j.1365-313X.2008.03438.x. PubMed DOI
O’Connor SE, Maresh JJ. Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 2006;23:532–547. doi: 10.1039/b512615k. PubMed DOI
Qu Y, Safonova O, De Luca V. Completion of the canonical pathway for assembly of anticancer drugs vincristine/vinblastine in Catharanthus roseus. Plant J. 2018;97:257–266. doi: 10.1111/tpj.14111. PubMed DOI
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. 2015;112:6224–6229. doi: 10.1073/pnas.1501821112. PubMed DOI PMC
Qu Y, et al. Geissoschizine synthase controls flux in the formation of monoterpenoid indole alkaloids in a Catharanthus roseus mutant. Planta. 2017;25:1–10. PubMed
Qu Y, et al. Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19 E-geissoschizine. Proc. Natl Acad. Sci. 2018;21:201719979–6. PubMed PMC
Caputi L, et al. Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle. Science. 2018;360:1235–1239. doi: 10.1126/science.aat4100. PubMed DOI
Brown S, Clastre M, Courdavault V, O’Connor SE. De novo production of the plant-derived alkaloid strictosidine in yeast. Proc. Natl Acad. Sci. 2015;112:3205–3210. doi: 10.1073/pnas.1423555112. PubMed DOI PMC
Tatsis EC, et al. A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate. Nat. Commun. 2017;8:1–9. doi: 10.1038/s41467-017-00154-x. PubMed DOI PMC
Payne RME, et al. An NPF transporter exports a central monoterpene indole alkaloid intermediate from the vacuole. Nat. Plants. 2017;3:1–9. doi: 10.1038/nplants.2016.208. PubMed DOI PMC
Cruz PL, et al. Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories. Molecules. 2021;26:3596. doi: 10.3390/molecules26123596. PubMed DOI PMC
Yamamoto K, et al. The complexity of intercellular localisation of alkaloids revealed by single-cell metabolomics. N. phytologist. 2019;224:848–859. doi: 10.1111/nph.16138. PubMed DOI
Sottomayor M, Barceló AR. Peroxidase from Catharanthus roseus (L.) G. Don and the biosynthesis of alpha-3’,4’-anhydrovinblastine: a specific role for a multifunctional enzyme. Protoplasma. 2003;222:97–105. doi: 10.1007/s00709-003-0003-9. PubMed DOI
Roepke J, et al. Vinca drug components accumulate exclusively in leaf exudates of Madagascar periwinkle. Proc. Natl Acad. Sci. 2010;107:15287–15292. doi: 10.1073/pnas.0911451107. PubMed DOI PMC
Atta-Ur-Rahman MS, Albert K. Structural Studies on Vindolinine. Z. Naturforsch. 1986;41:386–392. doi: 10.1515/znb-1986-0316. DOI
Durham LJ, Shoolery JN, Djerassi C. Reinvestigation of the Proton Resonance Spectrum of Vindolinine at 300 MHz. Proc. Natl Acad. Sci. 1974;71:3797–3799. doi: 10.1073/pnas.71.10.3797. PubMed DOI PMC
Kam T-S, Choo Y-M. Venalstonine and dioxokopsan derivatives from Kopsia fruticosa. Phytochemistry. 2004;65:2119–2122. doi: 10.1016/j.phytochem.2004.03.027. PubMed DOI
Lim K-H, et al. Biologically active indole alkaloids from Kopsia arborea. J. Nat. Products. 2007;70:1302–1307. doi: 10.1021/np0702234. PubMed DOI
Murata J, Roepke J, Gordon H, De Luca V. The leaf epidermome of Catharanthus roseus reveals its biochemical specialization. Plant Cell. 2008;20:524–542. doi: 10.1105/tpc.107.056630. PubMed DOI PMC
Levac D, Murata J, Kim WS, De Luca V. Application of carborundum abrasion for investigating the leaf epidermis: molecular cloning of Catharanthus roseus 16-hydroxytabersonine-16-O-methyltransferase. Plant J. 2008;53:225–236. doi: 10.1111/j.1365-313X.2007.03337.x. PubMed DOI
St-Pierre B, Vazquez-Flota F, De Luca V. Multicellular compartmentation of catharanthus roseus alkaloid biosynthesis predicts intercellular translocation of a pathway intermediate. Plant Cell. 1999;11:887–900. doi: 10.1105/tpc.11.5.887. PubMed DOI PMC
Courdavault V, et al. A look inside an alkaloid multisite plant: the Catharanthus logistics. Curr. Opin. Plant Biol. 2014;19:43–50. doi: 10.1016/j.pbi.2014.03.010. PubMed DOI
De Carolis E, De Luca V. A novel 2-oxoglutarate-dependent dioxygenase involved in vindoline biosynthesis: characterization, purification and kinetic properties. Plant Cell, Tissue Organ Cult. 1994;38:281–287. doi: 10.1007/BF00033888. DOI
Laflamme P, St-Pierre B, De Luca V. Molecular and biochemical analysis of a Madagascar periwinkle root-specific minovincinine-19-hydroxy-o-acetyltransferase. Plant Physiol. 2001;125:189–198. doi: 10.1104/pp.125.1.189. PubMed DOI PMC
Buckingham J., Baggaley K. H., Roberts A. D., & Szabó L. F. Dictionary of Alkaloids Second Eition with CD-ROM. (CRC Press 2010).
Scott AI. Biogenetic-type synthesis of the indole alkaloids. Bioorg. Chem. 1974;3:398–429. doi: 10.1016/0045-2068(74)90011-X. DOI
Edge A, et al. A tabersonine 3-reductase Catharanthus roseus mutant accumulates vindoline pathway intermediates. Planta. 2017;25:1–15. PubMed
Xiao M, et al. Transcriptome analysis based on next-generation sequencing of non-model plants producing specialized metabolites of biotechnological interest. J. Biotechnol. 2013;166:122–134. doi: 10.1016/j.jbiotec.2013.04.004. PubMed DOI
Hagel JM, Facchini PJ. Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy. Nat. Chem. Biol. 2010;6:273–275. doi: 10.1038/nchembio.317. PubMed DOI
Farrow SC, et al. Biosynthesis of an Anti-Addiction Agent from the Iboga Plant. J. Am. Chem. Soc. 2019;141:12979–12983. doi: 10.1021/jacs.9b05999. PubMed DOI PMC
Caputi L, et al. Structural basis of cycloaddition in biosynthesis of iboga and aspidosperma alkaloids. Nat. Chem. Biol. 2020;16:1–8. doi: 10.1038/s41589-019-0460-x. PubMed DOI PMC
Bugg TDH. Dioxygenase enzymes: Catalytic mechanisms and chemical models. Tetrahedron. 2003;59:7075–7101. doi: 10.1016/S0040-4020(03)00944-X. DOI
Martinez S, Hausinger RP. Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases. J. Biol. Chem. 2015;290:20702–20711. doi: 10.1074/jbc.R115.648691. PubMed DOI PMC
Dewhist RA, Fry SC. The oxidation of dehydroascorbic acid and 2,3-diketogulonate by distinct reactive oxygen species. Biochem J. 2018;475:3451–3470. doi: 10.1042/BCJ20180688. PubMed DOI PMC
Kim CY, et al. The chloroalkaloid (−)-acutumine is biosynthesized via a Fe(II)- and 2-oxoglutarate-dependent halogenase in Menispermaceae plants. Nat. Commun. 2020;11:1867. doi: 10.1038/s41467-020-15777-w. PubMed DOI PMC
Topf M, et al. The Unusual Bifunctional Catalysis of Epimerization and Desaturation by Carbapenem Synthase. J. Am. Chem. Soc. 2004;126:9932–9933. doi: 10.1021/ja047899v. PubMed DOI
Chang W, et al. Mechanism of the C5 Stereo-inversion Reaction in the Biosynthesis of Carbapenem Antibiotics. Science. 2014;343:1140–1144. doi: 10.1126/science.1248000. PubMed DOI PMC
Matsuda Y, Wakimoto T, Mori T, Awakawa T, Abe I. Complete Biosynthetic Pathway of Anditomin: Nature’s Sophisticated Synthetic Route to a Complex Fungal Meroterpenoid. J. Am. Chem. Soc. 2014;136:15326–15336. doi: 10.1021/ja508127q. PubMed DOI
Williams D, Qu Y, Simionescu R, De Luca V. The assembly of (+)‐vincadifformine‐ and (−)‐tabersonine‐derived monoterpenoid indole alkaloids in Catharanthus roseus involves separate branch pathways. Plant J. 2019;99:626–636. doi: 10.1111/tpj.14346. PubMed DOI