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Structural investigation of heteroyohimbine alkaloid synthesis reveals active site elements that control stereoselectivity.

<div class='caption-title'>Heteroyohimbine alkaloid biosynthesis.</div>
<div class='caption-title'>LC-MS analysis of active MDR candidates against strictosidine aglycone.</div>
<div class='caption-title'>Sequence alignment of Catharanthus roseus HYS enzymes and Populus tremuloides SAD</div>
Stavrinides A, Tatsis EC, Caputi L, Foureau E, Stevenson CE, Lawson DM, Courdavault V, O'Connor SE
OpenAccess logo Nat Commun 7 12116 (2016)
Related entries: 5fi3, 5fi5, 5h81, 5h82

Cited: 38 times
EuropePMC logo PMID: 27418042

Abstract

Plants produce an enormous array of biologically active metabolites, often with stereochemical variations on the same molecular scaffold. These changes in stereochemistry dramatically impact biological activity. Notably, the stereoisomers of the heteroyohimbine alkaloids show diverse pharmacological activities. We reported a medium chain dehydrogenase/reductase (MDR) from Catharanthus roseus that catalyses formation of a heteroyohimbine isomer. Here we report the discovery of additional heteroyohimbine synthases (HYSs), one of which produces a mixture of diastereomers. The crystal structures for three HYSs have been solved, providing insight into the mechanism of reactivity and stereoselectivity, with mutation of one loop transforming product specificity. Localization and gene silencing experiments provide a basis for understanding the function of these enzymes in vivo. This work sets the stage to explore how MDRs evolved to generate structural and biological diversity in specialized plant metabolism and opens the possibility for metabolic engineering of new compounds based on this scaffold.

Articles - 5h83 mentioned but not cited (2)

  1. Structural investigation of heteroyohimbine alkaloid synthesis reveals active site elements that control stereoselectivity. Stavrinides A, Tatsis EC, Caputi L, Foureau E, Stevenson CE, Lawson DM, Courdavault V, O'Connor SE. Nat Commun 7 12116 (2016)
  2. Expansion of the Catalytic Repertoire of Alcohol Dehydrogenases in Plant Metabolism. Langley C, Tatsis E, Hong B, Nakamura Y, Paetz C, Stevenson CEM, Basquin J, Lawson DM, Caputi L, O'Connor SE. Angew Chem Int Ed Engl 61 e202210934 (2022)


Reviews citing this publication (4)

  1. Transcriptional Regulation and Transport of Terpenoid Indole Alkaloid in Catharanthus roseus: Exploration of New Research Directions. Liu J, Cai J, Wang R, Yang S. Int J Mol Sci 18 E53 (2016)
  2. Terpenoid indole alkaloid biosynthesis in Catharanthus roseus: effects and prospects of environmental factors in metabolic engineering. Liu Y, Patra B, Singh SK, Paul P, Zhou Y, Li Y, Wang Y, Pattanaik S, Yuan L. Biotechnol Lett 43 2085-2103 (2021)
  3. Biosynthesis and synthetic biology of psychoactive natural products. Jamieson CS, Misa J, Tang Y, Billingsley JM. Chem Soc Rev 50 6950-7008 (2021)
  4. Advances in Metabolic Engineering of Plant Monoterpene Indole Alkaloids. Salim V, Jarecki SA, Vick M, Miller R. Biology (Basel) 12 1056 (2023)

Articles citing this publication (32)

  1. Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle. Caputi L, Franke J, Farrow SC, Chung K, Payne RME, Nguyen TD, Dang TT, Soares Teto Carqueijeiro I, Koudounas K, Dugé de Bernonville T, Ameyaw B, Jones DM, Vieira IJC, Courdavault V, O'Connor SE. Science 360 1235-1239 (2018)
  2. A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate. Tatsis EC, Carqueijeiro I, Dugé de Bernonville T, Franke J, Dang TT, Oudin A, Lanoue A, Lafontaine F, Stavrinides AK, Clastre M, Courdavault V, O'Connor SE. Nat Commun 8 316 (2017)
  3. Cross-family transcription factor interaction between MYC2 and GBFs modulates terpenoid indole alkaloid biosynthesis. Sui X, Singh SK, Patra B, Schluttenhofer C, Guo W, Pattanaik S, Yuan L. J Exp Bot 69 4267-4281 (2018)
  4. A BAHD acyltransferase catalyzing 19-O-acetylation of tabersonine derivatives in roots of Catharanthus roseus enables combinatorial synthesis of monoterpene indole alkaloids. Carqueijeiro I, Dugé de Bernonville T, Lanoue A, Dang TT, Teijaro CN, Paetz C, Billet K, Mosquera A, Oudin A, Besseau S, Papon N, Glévarec G, Atehortùa L, Clastre M, Giglioli-Guivarc'h N, Schneider B, St-Pierre B, Andrade RB, O'Connor SE, Courdavault V. Plant J 94 469-484 (2018)
  5. Geissoschizine synthase controls flux in the formation of monoterpenoid indole alkaloids in a Catharanthus roseus mutant. Qu Y, Thamm AMK, Czerwinski M, Masada S, Kim KH, Jones G, Liang P, De Luca V. Planta 247 625-634 (2018)
  6. Unraveling the structural and chemical features of biological short hydrogen bonds. Zhou S, Wang L. Chem Sci 10 7734-7745 (2019)
  7. Structural basis for divergent and convergent evolution of catalytic machineries in plant aromatic amino acid decarboxylase proteins. Torrens-Spence MP, Chiang YC, Smith T, Vicent MA, Wang Y, Weng JK. Proc Natl Acad Sci U S A 117 10806-10817 (2020)
  8. Two Tabersonine 6,7-Epoxidases Initiate Lochnericine-Derived Alkaloid Biosynthesis in Catharanthus roseus. Carqueijeiro I, Brown S, Chung K, Dang TT, Walia M, Besseau S, Dugé de Bernonville T, Oudin A, Lanoue A, Billet K, Munsch T, Koudounas K, Melin C, Godon C, Razafimandimby B, de Craene JO, Glévarec G, Marc J, Giglioli-Guivarc'h N, Clastre M, St-Pierre B, Papon N, Andrade RB, O'Connor SE, Courdavault V. Plant Physiol 177 1473-1486 (2018)
  9. Improved virus-induced gene silencing allows discovery of a serpentine synthase gene in Catharanthus roseus. Yamamoto K, Grzech D, Koudounas K, Stander EA, Caputi L, Mimura T, Courdavault V, O'Connor SE. Plant Physiol 187 846-857 (2021)
  10. Alternative splicing creates a pseudo-strictosidine β-d-glucosidase modulating alkaloid synthesis in Catharanthus roseus. Carqueijeiro I, Koudounas K, Dugé de Bernonville T, Sepúlveda LJ, Mosquera A, Bomzan DP, Oudin A, Lanoue A, Besseau S, Lemos Cruz P, Kulagina N, Stander EA, Eymieux S, Burlaud-Gaillard J, Blanchard E, Clastre M, Atehortùa L, St-Pierre B, Giglioli-Guivarc'h N, Papon N, Nagegowda DA, O'Connor SE, Courdavault V. Plant Physiol 185 836-856 (2021)
  11. Biosynthesis of strychnine. Hong B, Grzech D, Caputi L, Sonawane P, López CER, Kamileen MO, Hernández Lozada NJ, Grabe V, O'Connor SE. Nature 607 617-622 (2022)
  12. Identifying Genes Involved in alkaloid Biosynthesis in Vinca minor Through Transcriptomics and Gene Co-Expression Analysis. Stander EA, Sepúlveda LJ, Dugé de Bernonville T, Carqueijeiro I, Koudounas K, Lemos Cruz P, Besseau S, Lanoue A, Papon N, Giglioli-Guivarc'h N, Dirks R, O'Connor SE, Atehortùa L, Oudin A, Courdavault V. Biomolecules 10 E1595 (2020)
  13. Discovery of a Short-Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid. Stavrinides AK, Tatsis EC, Dang TT, Caputi L, Stevenson CEM, Lawson DM, Schneider B, O'Connor SE. Chembiochem 19 940-948 (2018)
  14. Methyljasmonate Elicitation Increases Terpenoid Indole Alkaloid Accumulation in Rhazya stricta Hairy Root Cultures. Akhgari A, Laakso I, Maaheimo H, Choi YH, Seppänen-Laakso T, Oksman-Caldentey KM, Rischer H. Plants (Basel) 8 E534 (2019)
  15. Reconstitution of monoterpene indole alkaloid biosynthesis in genome engineered Nicotiana benthamiana. Dudley QM, Jo S, Guerrero DAS, Chhetry M, Smedley MA, Harwood WA, Sherden NH, O'Connor SE, Caputi L, Patron NJ. Commun Biol 5 949 (2022)
  16. Short hydrogen bonds enhance nonaromatic protein-related fluorescence. Stephens AD, Qaisrani MN, Ruggiero MT, Díaz Mirón G, Morzan UN, González Lebrero MC, Jones STE, Poli E, Bond AD, Woodhams PJ, Kleist EM, Grisanti L, Gebauer R, Zeitler JA, Credgington D, Hassanali A, Kaminski Schierle GS. Proc Natl Acad Sci U S A 118 e2020389118 (2021)
  17. Single-cell multi-omics in the medicinal plant Catharanthus roseus. Li C, Wood JC, Vu AH, Hamilton JP, Rodriguez Lopez CE, Payne RME, Serna Guerrero DA, Gase K, Yamamoto K, Vaillancourt B, Caputi L, O'Connor SE, Robin Buell C. Nat Chem Biol 19 1031-1041 (2023)
  18. The Vinca minor genome highlights conserved evolutionary traits in monoterpene indole alkaloid synthesis. Stander EA, Cuello C, Birer-Williams C, Kulagina N, Jansen HJ, Carqueijeiro I, Méteignier LV, Vergès V, Oudin A, Papon N, Dirks RP, Jensen MK, O'Connor SE, Dugé de Bernonville T, Besseau S, Courdavault V. G3 (Bethesda) 12 jkac268 (2022)
  19. Conversion of Cytochrome P450 2D6 of Human Into a FRET-Based Tool for Real-Time Monitoring of Ajmalicine in Living Cells. Ambrin G, Ahmad M, Alqarawi AA, Hashem A, Abd Allah EF, Ahmad A. Front Bioeng Biotechnol 7 375 (2019)
  20. Recycling Upstream Redox Enzymes Expands the Regioselectivity of Cycloaddition in Pseudo-Aspidosperma Alkaloid Biosynthesis. Kamileen MO, DeMars MD, Hong B, Nakamura Y, Paetz C, Lichman BR, Sonawane PD, Caputi L, O'Connor SE. J Am Chem Soc 144 19673-19679 (2022)
  21. Structure-function analyses of two plant meso-diaminopimelate decarboxylase isoforms reveal that active-site gating provides stereochemical control. Crowther JM, Cross PJ, Oliver MR, Leeman MM, Bartl AJ, Weatherhead AW, North RA, Donovan KA, Griffin MDW, Suzuki H, Hudson AO, Kasanmascheff M, Dobson RCJ. J Biol Chem 294 8505-8515 (2019)
  22. Subfunctionalization of Paralog Transcription Factors Contributes to Regulation of Alkaloid Pathway Branch Choice in Catharanthus roseus. Colinas M, Pollier J, Vaneechoutte D, Malat DG, Schweizer F, De Milde L, De Clercq R, Guedes JG, Martínez-Cortés T, Molina-Hidalgo FJ, Sottomayor M, Vandepoele K, Goossens A. Front Plant Sci 12 687406 (2021)
  23. Deciphering and reprogramming the cyclization regioselectivity in bifurcation of indole alkaloid biosynthesis. Wang Z, Xiao Y, Wu S, Chen J, Li A, Tatsis EC. Chem Sci 13 12389-12395 (2022)
  24. Directed Biosynthesis of Mitragynine Stereoisomers. Schotte C, Jiang Y, Grzech D, Dang TT, Laforest LC, León F, Mottinelli M, Nadakuduti SS, McCurdy CR, O'Connor SE. J Am Chem Soc 145 4957-4963 (2023)
  25. Directed Biosynthesis of New to Nature Alkaloids in a Heterologous Nicotiana benthamiana Expression Host. Boccia M, Grzech D, Lopes AA, O'Connor SE, Caputi L. Front Plant Sci 13 919443 (2022)
  26. Identification and Characterization of Transcription Factors Regulating Terpenoid Indole Alkaloid Biosynthesis in Catharanthus roseus. Singh SK, Patra B, Singleton JJ, Liu Y, Paul P, Sui X, Suttipanta N, Pattanaik S, Yuan L. Methods Mol Biol 2505 203-221 (2022)
  27. Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast. Bradley SA, Lehka BJ, Hansson FG, Adhikari KB, Rago D, Rubaszka P, Haidar AK, Chen L, Hansen LG, Gudich O, Giannakou K, Lengger B, Gill RT, Nakamura Y, de Bernonville TD, Koudounas K, Romero-Suarez D, Ding L, Qiao Y, Frimurer TM, Petersen AA, Besseau S, Kumar S, Gautron N, Melin C, Marc J, Jeanneau R, O'Connor SE, Courdavault V, Keasling JD, Zhang J, Jensen MK. Nat Chem Biol 19 1551-1560 (2023)
  28. De novo biosynthesis of antiarrhythmic alkaloid ajmaline. Guo J, Gao D, Lian J, Qu Y. Nat Commun 15 457 (2024)
  29. Discovering Dynamic Plant Enzyme Complexes in Yeast for Kratom Alkaloid Pathway Identification. Wu Y, Liu C, Koganitsky A, Gong FL, Li S. Angew Chem Int Ed Engl 62 e202307995 (2023)
  30. Gene discovery in plant metabolism: Listening to the sound of silence, but where? Nguyen TD. Plant Physiol 187 670-672 (2021)
  31. The Rauvolfia tetraphylla genome suggests multiple distinct biosynthetic routes for yohimbane monoterpene indole alkaloids. Stander EA, Lehka B, Carqueijeiro I, Cuello C, Hansson FG, Jansen HJ, Dugé De Bernonville T, Birer Williams C, Vergès V, Lezin E, Lorensen MDBB, Dang TT, Oudin A, Lanoue A, Durand M, Giglioli-Guivarc'h N, Janfelt C, Papon N, Dirks RP, O'connor SE, Jensen MK, Besseau S, Courdavault V. Commun Biol 6 1197 (2023)
  32. The leaf idioblastome of the medicinal plant Catharanthus roseus is associated with stress resistance and alkaloid metabolism. Guedes JG, Ribeiro R, Carqueijeiro I, Guimarães AL, Bispo C, Archer J, Azevedo H, Fonseca NA, Sottomayor M. J Exp Bot 75 274-299 (2024)


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