The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

Planta Medica

Volumn 84, Issue 12-13, 2018, Pages 855-873

  Scossa, Federico ^a,b   Benina, Maria ^c   Alseekh, Saleh ^a   Zhang, Youjun ^a,c   Fernie, Alisdair R ^a  

^a MAX PLANCK INSTITUTE OF MOLECULAR PLANT PHYSIOLOGY   (Germany)

^b ISTITUTO NAZIONALE DELLA NUTRIZIONE   (Italy)

^c CENTER OF PLANT SYSTEMS BIOLOGY AND BIOTECHNOLOGY   (Bulgaria)

Author keywords

alkaloids; Apocynaceae; artemisinin; caffeine; cannabinoids; Catharanthus roseus; ginseng; Papaver somniferum; Papaveraceae; taxol

Indexed keywords

ARTEMISININ; BENZOISOQUINOLINE ALKALOID; CAFFEINE; CANNABINOID DERIVATIVE; DRUG METABOLITE; GINSENOSIDE; INDOLE ALKALOID; ISOQUINOLINE; MONOTERPENOID INDOLE ALKALOID; NATURAL PRODUCT; OPIATE; PACLITAXEL; PLANT MEDICINAL PRODUCT; UNCLASSIFIED DRUG; WITHANOLIDE; ALKALOID; BIOLOGICAL PRODUCT; PHYTOCHEMICAL;

ANEMIA; BIOINFORMATICS; BIOSYNTHESIS; CELL COMPARTMENTALIZATION; COST EFFECTIVENESS ANALYSIS; DRUG RESEARCH; DRUG STRUCTURE; FATIGUE; HEART DISEASE; HIGH THROUGHPUT SCREENING; HUMAN; MALARIA; MALIGNANT NEOPLASM; MEDICINAL PLANT; METABOLOMICS; NEXT GENERATION SEQUENCING; NONHUMAN; PAIN; PLANT GENE; PLANT METABOLISM; REVIEW; RHEUMATIC DISEASE; SYSTEMS BIOLOGY; TRADITIONAL MEDICINE; CHEMISTRY; DNA SEQUENCE; GENETICS; HIGH THROUGHPUT SEQUENCING; METABOLISM; SECONDARY METABOLISM;

ALKALOIDS; BIOLOGICAL PRODUCTS; BIOSYNTHETIC PATHWAYS; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; METABOLOMICS; PHYTOCHEMICALS; PLANTS, MEDICINAL; SECONDARY METABOLISM; SEQUENCE ANALYSIS, DNA;

EID: 85048001771     PISSN: 00320943     EISSN: 14390221     Source Type: Journal    
DOI: 10.1055/a-0630-1899     Document Type: Review

References (304)

1. Hardy K. Buckley S. Collins M. J. Estalrrich A. Brothwell D. Copeland L. Garcia-Tabernero A. Garcia-Vargas S. de la Rasilla M. Lalueza-Fox C. Huguet R. Bastir M. Santamaria D. Madella M. Wilson J. Cortes A. F. Rosas A. Neanderthal medics? Evidence for food, cooking, and medicinal plants entrapped in dental calculus. Naturwissenschaften: 2012; 99 617 626
2. Krikler D. M. The foxglove, The old woman from Shropshire and William Withering. J Am Coll Cardiol: 1985; 5 A3 A9
3. Somberg J. Greenfield B. Tepper D. Digitalis - historical development in clinical medicine. J Clin Pharmacol: 1985; 25 484 489
4. Brook K. Bennett J. Desai S. P. The chemical history of morphine: an 8000-year journey, from resin to de-novo synthesis. J Anesth Hist: 2017; 3 50 55
5. Wurtzel E. T. Kutchan T. M. Plant metabolism, the diverse chemistry set of the future. Science: 2016; 353 1232 1236
6. Harvey A. L. Edrada-Ebel R. Quinn R. J. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov: 2015; 14 111 129
7. Buckingham J. Dictionary of natural Products. Abingdon Taylor & Francis: 1993
8. Newman D. J. Cragg G. M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod: 2012; 75 311 335
9. Rishton G. M. Natural products as a robust source of new drugs and drug leads: past successes and present day issues. Am J Cardio: 2008; 101 43D 49D
10. Barker A. Kettle J. G. Nowak T. Pease J. E. Expanding medicinal chemistry space. Drug Discov Today: 2013; 18 298 304
11. Skirycz A. Kierszniowska S. Meret M. Willmitzer L. Tzotzos G. Medicinal bioprospecting of the Amazon rainforest: a modern Eldorado? Trends Biotechnol: 2016; 34 781 790
12. O'Connor S. E. Engineering of secondary metabolism. Annu Rev Genet: 2015; 49 71 94
13. Dastmalchi M. Park M. R. Morris J. S. Facchini P. Family portraits: the enzymes behind benzylisoquinoline alkaloid diversity. Phytochem Rev: 2018; 17 249 277
14. Pan Q. Mustafa N. R. Tang K. Choi Y. H. Verpoorte R. Monoterpenoid indole alkaloids biosynthesis and its regulation in Catharanthus roseus: a literature review from genes to metabolites. Phytochem Rev: 2016; 15 221 250
15. Thamm A. MK. Qu Y. De Luca V. Discovery and metabolic engineering of iridoid/secoiridoid and monoterpenoid indole alkaloid biosynthesis. Phytochem Rev: 2016; 15 339 361
16. Radwan M. M. Wanas A. S. Chandra S. ElSohly M. A. Natural Cannabinoids of Cannabis and Methods of Analysis. In: Chandra S. Lata H. ElSohly M. A. eds. Cannabis sativa L. - Botany and Biotechnology. Cham Springer International Publishing: 2017; 161 182
17. Ashihara H. Mizuno K. Yokota T. Crozier A. Xanthine Alkaloids: Occurrence, Biosynthesis, and Function in Plants. In: Kinghorn A. D. Falk H. Gibbons S. Kobayashi J. I. eds. Progress in the Chemistry of organic natural Products 105. Cham Springer International Publishing: 2017; 1 88
18. Kim Y. J. Zhang D. B. Yang D. C. Biosynthesis and biotechnological production of ginsenosides. Biotechnol Adv: 2015; 33 717 735
19. Yang B. Y. Xia Y. G. Pan J. Liu Y. Wang Q. H. Kuang H. X. Phytochemistry and biosynthesis of δ -lactone withanolides. Phytochem Rev: 2016; 15 771 797
20. Xie D. Y. Ma D. M. Judd R. Jones A. L. Artemisinin biosynthesis in Artemisia annua and metabolic engineering: questions, challenges, and perspectives. Phytochem Rev: 2016; 15 1093 1114
21. Croteau R. Ketchum R. EB. Long R. M. Kaspera R. Wildung M. R. Taxol biosynthesis and molecular genetics. Phytochem Rev: 2006; 5 75 97
22. Calvin M. Benson A. A. The path of carbon in photosynthesis. Science: 1948; 107 476 480
23. Benson A. Calvin M. The dark reductions of photosynthesis. Science: 1947; 105 648 649
24. Benson A. A. Calvin M. Carbon dioxide fixation by green plants. Annu Rev Plant Phys: 1950; 1 25 42
25. Hartmann T. From waste products to ecochemicals: fifty years research of plant secondary metabolism. Phytochemistry: 2007; 68 2831 2846
26. Kim J. Buell C. R. A revolution in plant metabolism: genome-enabled pathway discovery. Plant Physiol: 2015; 169 1532 1539
27. Fernie A. R. Pichersky E. Focus issue on metabolism: metabolites, metabolites everywhere. Plant Physiol: 2015; 169 1421 1423
28. Xu S. Q. Brockmoller T. Navarro-Quezada A. Kuhl H. Gase K. Ling Z. H. Zhou W. W. Kreitzer C. Stanke M. Tang H. B. Lyons E. Pandey P. Pandey S. P. Timmermann B. Gaquerel E. Baldwin I. T. Wild tobacco genomes reveal the evolution of nicotine biosynthesis. Proc Natl Acad Sci U S A: 2017; 114 6133 6138
29. Huang R. Q. O'Donnell A. J. Barboline J. J. Barkman T. J. Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes. Proc Natl Acad Sci U S A: 2016; 113 10613 10618
30. Facchini P. J. De Luca V. Opium poppy and Madagascar periwinkle: model non-model systems to investigate alkaloid biosynthesis in plants. Plant J: 2008; 54 763 784
31. Sun M. Lou W. Chun J. Y. Cho D. S. Nadiminty N. Evans C. P. Chen J. Yue J. Zhou Q. Gao A. C. Sanguinarine suppresses prostate tumor growth and inhibits survivin expression. Genes Cancer: 2010; 1 283 292
32. Sun M. Chun J. Lou W. Gao A. Sanguinarine is a novel inhibitor of survivin and inhibits the growth of prostate cancer cells. J Urology: 2010; 183 E459
33. Ballantyne J. C. Shin N. S. Efficacy of opioids for chronic pain: a review of the evidence. Clin Journal Pain: 2008; 24 469 478
34. Battersby A. R. Harper B. JT. Rate study on the incorporation of tyrosine into morphine, codeine and thebaine. Tetrahedron Lett: 1960; 1 21 24
35. Leete E. Biosynthesis of alkaloids. Science: 1965; 147 1000 1006
36. Rueffer M. Elshagi H. Nagakura N. Zenk M. H. (S)-Norlaudanosoline synthase - the 1st enzyme in the benzylisoquinoline biosynthetic-pathway. FEBS Lett: 1981; 129 5 9
37. Samanani N. Liscombe D. K. Facchini P. J. Molecular cloning and characterization of norcoclaurine synthase, an enzyme catalyzing the first committed step in benzylisoquinoline alkaloid biosynthesis. Plant J: 2004; 40 302 313
38. Morishige T. Tsujita T. Yamada Y. Sato F. Molecular characterization of the S-adenosyl-L-methionine: 3′-hydroxy-N-methylcoclaurine 4′- O -methyltransferase involved in isoquinoline alkaloid biosynthesis in Coptis japonica. J Biol Chem: 2000; 275 23398 23405
39. Ounaroon A. Decker G. Schmidt J. Lottspeich F. Kutchan T. M. (R,S)-Reticuline 7- O -methyltransferase and (R,S)-norcoclaurine 6- O -methyltransferase of Papaver somniferum - cDNA cloning and characterization of methyl transfer enzymes of alkaloid biosynthesis in opium poppy. Plant J: 2003; 36 808 819
40. Choi K. B. Morishige T. Shitan N. Yazaki K. Sato F. Molecular cloning and characterization of coclaurine N -methyltransferase from cultured cells of Coptis japonica. J Biol Chem: 2002; 277 830 835
41. Hagel J. M. Facchini P. J. Dioxygenases catalyze the O -demethylation steps of morphine biosynthesis in opium poppy. Nat Chem Biol: 2010; 6 273 275
42. Desgagne-Penix I. Khan M. F. Schriemer D. C. Cram D. Nowak J. Facchini P. J. Integration of deep transcriptome and proteome analyses reveals the components of alkaloid metabolism in opium poppy cell cultures. BMC Plant Biol: 2010; 10 252
43. Desgagne-Penix I. Farrow S. C. Cram D. Nowak J. Facchini P. J. Integration of deep transcript and targeted metabolite profiles for eight cultivars of opium poppy. Plant Mol Biol: 2012; 79 295 313
44. Winzer T. Kern M. King A. J. Larson T. R. Teodor R. I. Donninger S. L. Li Y. Dowle A. A. Cartwright J. Bates R. Ashford D. Thomas J. Walker C. Bowser T. A. Graham I. A. Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein. Science: 2015; 349 309 312
45. Farrow S. C. Hagel J. M. Beaudoin G. AW. Burns D. C. Facchini P. J. Stereochemical inversion of (S)-reticuline by a cytochrome P450 fusion in opium poppy. Nat Chem Biol: 2015; 11 728 732
46. Hoffmann I. Oliw E. H. Discovery of a linoleate 9S-dioxygenase and an allene oxide synthase in a fusion protein of Fusarium oxysporum. J Lipid Res: 2013; 54 3471 3480
47. Ye K. Q. Ke Y. Keshava N. Shanks J. Kapp J. A. Tekmal R. R. Petros J. Joshi H. C. Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. Proc Natl Acad Sci U S A: 1998; 95 1601 1606
48. Sung B. Ahn K. S. Aggarwal B. B. Noscapine, a benzylisoquinoline alkaloid, sensitizes leukemic cells to chemotherapeutic agents and cytokines by modulating the NF-kappa B signaling pathway. Cancer Res: 2010; 70 3259 3268
49. Battersby A. R. Foulkes D. M. Hirst M. Parry G. V. Staunton J. Alkaloid biosynthesis. Part XI. Studies related to formation and oxidation of reticuline in morphine biosynthesis. J Chem Soc C: 1968; 210 216
50. Winzer T. Gazda V. He Z. Kaminski F. Kern M. Larson T. R. Li Y. Meade F. Teodor R. Vaistij F. E. Walker C. Bowser T. A. Graham I. A. A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine. Science: 2012; 336 1704 1708
51. Nutzmann H. W. Huang A. C. Osbourn A. Plant metabolic clusters - from genetics to genomics. New Phytol: 2016; 211 771 789
52. Hudlicky T. Recent advances in process development for opiate-derived pharmaceutical agents. Can J Chem: 2015; 93 492 501
53. Thodey K. Galanie S. Smolke C. D. A microbial biomanufacturing platform for natural and semisynthetic opioids. Nat Chem Biol: 2014; 10 837 844
54. Galanie S. Thodey K. Trenchard I. J. Interrante M. F. Smolke C. D. Complete biosynthesis of opioids in yeast. Science: 2015; 349 1095 1100
55. Nakagawa A. Matsumura E. Koyanagi T. Katayama T. Kawano N. Yoshimatsu K. Yamamoto K. Kumagai H. Sato F. Minami H. Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli. Nat Commun: 2016; 7 10390
56. Fossati E. Ekins A. Narcross L. Zhu Y. Falgueyret J. P. Beaudoin G. AW. Facchini P. J. Martin V. JJ. Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae. Nat Commun: 2014; 5 3283
57. Bates D. Eastman A. Microtubule destabilising agents: far more than just antimitotic anticancer drugs. Brit J Clin Pharmacol: 2017; 83 255 268
58. Roepke J. Salim V. Wu M. Thamm A. MK. Murata J. Ploss K. Boland W. De Luca V. Vinca drug components accumulate exclusively in leaf exudates of Madagascar periwinkle. Proc Natl Acad Sci U S A: 2010; 107 15287 15292
59. St-Pierre B. Vazquez-Flota F. A. De Luca V. Multicellular compartmentation of Catharanthus roseus alkaloid biosynthesis predicts intercellular translocation of a pathway intermediate. Plant Cell: 1999; 11 887 900
60. Guirimand G. Guihur A. Ginis O. Poutrain P. Hericourt F. Oudin A. Lanoue A. St-Pierre B. Burlat V. Courdavault V. The subcellular organization of strictosidine biosynthesis in Catharanthus roseus epidermis highlights several trans-tonoplast translocations of intermediate metabolites. FEBS J: 2011; 278 749 763
61. Guirimand G. Guihur A. Poutrain P. Hericourt F. Mahroug S. St-Pierre B. Burlat V. Courdavault V. Spatial organization of the vindoline biosynthetic pathway in Catharanthus roseus. J Plant Physiol: 2011; 168 549 557
62. Vranova E. Coman D. Gruissem W. Network analysis of the MVA and MEP pathways for isoprenoid synthesis. Annu Rev Plant Biol: 2013; 64 665 700
63. Money T. Wright I. G. Mccapra F. Hall E. S. Scott A. I. Biosynthesis of indole alkaloids. Vindoline. J Am Chem Soc: 1968; 90 4144 4150
64. Miettinen K. Dong L. M. Navrot N. Schneider T. Burlat V. Pollier J. Woittiez L. van der Krol S. Lugan R. Ilc T. Verpoorte R. Oksman-Caldentey K. M. Martinoia E. Bouwmeester H. Goossens A. Memelink J. Werck-Reichhart D. The seco-iridoid pathway from Catharanthus roseus. Nat Commun: 2014; 5 3608
65. Salim V. Yu F. Altarejos J. De Luca V. Virus-induced gene silencing identifies Catharanthus roseus 7-deoxyloganic acid-7-hydroxylase, a step in iridoid and monoterpene indole alkaloid biosynthesis. Plant J: 2013; 76 754 765
66. Asada K. Salim V. Masada-Atsumi S. Edmunds E. Nagatoshi M. Terasaka K. Mizukami H. De Luca V. A 7-Deoxyloganetic acid glucosyltransferase contributes a key step in secologanin biosynthesis in Madagascar periwinkle. Plant Cell: 2013; 25 4123 4134
67. Salim V. Wiens B. Masada-Atsumi S. Yu F. De Luca V. 7-Deoxyloganetic acid synthase catalyzes a key 3 step oxidation to form 7-deoxyloganetic acid in Catharanthus roseus iridoid biosynthesis. Phytochemistry: 2014; 101 23 31
68. Geu-Flores F. Sherden N. H. Courdavault V. Burlat V. Glenn W. S. Wu C. Nims E. Cui Y. H. O'Connor S. E. An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis. Nature: 2012; 492 138 142
69. Mcknight T. D. Roessner C. A. Devagupta R. Scott A. I. Nessler C. L. Nucleotide-sequence of a cDNA-encoding the vacuolar protein strictosidine synthase from Catharanthus roseus. Nucleic Acids Res: 1990; 18 4939
70. Geerlings A. Ibanez M. ML. Memelink J. van der Heijden R. Verpoorte R. Molecular cloning and analysis of strictosidine beta-d-glucosidase, an enzyme in terpenoid indole alkaloid biosynthesis in Catharanthus roseus. J Biol Chem: 2000; 275 3051 3056
71. Tatsis E. C. Carqueijeiro I. de Bernonville T. D. Franke J. Dang T. TT. Oudin A. Lanoue A. Lafontaine F. Stavrinides A. K. Clastre M. Courdavault V. O'Connor S. E. A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate. Nat Commun: 2017; 8 316
72. Stavrinides A. Tatsis Evangelos C. Foureau E. Caputi L. Kellner F. Courdavault V. O'Connor S. E. Unlocking the diversity of alkaloids in Catharanthus roseus: nuclear localization suggests metabolic channeling in secondary metabolism. Chem Biol: 2015; 22 336 341
73. Besseau S. Kellner F. Lanoue A. Thamm A. MK. Salim V. Schneider B. Geu-Flores F. Hofer R. Guirimand G. Guihur A. Oudin A. Glevarec G. Foureau E. Papon N. Clastre M. Giglioli-Guivarc'h N. St-Pierre B. Werck-Reichhart D. Burlat V. De Luca V. O'Connor S. E. Courdavault V. A pair of tabersonine 16-hydroxylases initiates the synthesis of vindoline in an organ-dependent manner in Catharanthus roseus. Plant Physiol: 2013; 163 1792 1803
74. Kellner F. Kim J. Clavijo B. J. Hamilton J. P. Childs K. L. Vaillancourt B. Cepela J. Habermann M. Steuernagel B. Clissold L. McLay K. Buell C. R. O'Connor S. E. Genome-guided investigation of plant natural product biosynthesis. Plant J: 2015; 82 680 692
75. Qu Y. Easson M. L. Froese J. Simionescu R. Hudlicky T. De Luca V. Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast. Proc Natl Acad Sci U S A: 2015; 112 6224 6229
76. Meijer A. H. Dewaal A. Verpoorte R. Purification of the cytochrome-P-450 enzyme geraniol 10-hydroxylase from cell-cultures of Catharanthus roseus. J Chromatogr: 1993; 635 237 249
77. Collu G. Unver N. Peltenburg-Looman A. MG. van der Heijden R. Verpoorte R. Memelink J. Geraniol 10-hydroxylase, a cytochrome P450 enzyme involved in terpenoid indole alkaloid biosynthesis. FEBS Lett: 2001; 508 215 220
78. Luijendijk T. JC. Stevens L. H. Verpoorte R. Purification and characterisation of strictosidine beta-D-glucosidase from Catharanthus roseus cell suspension cultures. Plant Physiol Bioch: 1998; 36 419 425
79. Rischer H. Oresic M. Seppanen-Laakso T. Katajamaa M. Lammertyn F. Ardiles-Diaz W. Van Montagu M. CE. Inze D. Oksman-Caldentey K. M. Goossens A. Gene-to-metabolite networks for terpenoid indole alkaloid biosynthesis in Catharanthus roseus cells. Proc Natl Acad Sci U S A: 2006; 103 5614 5619
80. 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
81. Gongora-Castillo E. Childs K. L. Fedewa G. Hamilton J. P. Liscombe D. K. Magallanes-Lundback M. Mandadi K. K. Nims E. Runguphan W. Vaillancourt B. Varbanova-Herde M. DellaPenna D. McKnight T. D. O'Connor S. Buell C. R. Development of transcriptomic resources for interrogating the biosynthesis of monoterpene indole alkaloids in medicinal plant species. PLoS One: 2012; 7 e52506
82. Van Moerkercke A. Fabris M. Pollier J. Baart G. JE. Rombauts S. Hasnain G. Rischer H. Memelink J. Oksman-Caldentey K. M. Goossens A. CathaCyc, a metabolic pathway database built from Catharanthus roseus RNA-seq data. Plant Cell Physiol: 2013; 54 673 685
83. Xiao M. Zhang Y. Chen X. Lee E. J. Barber C. JS. Chakrabarty R. Desgagne-Penix I. Haslam T. M. Kim Y. B. Liu E. W. MacNevin G. Masada-Atsumi S. Reed D. W. Stout J. M. Zerbe P. Zhang Y. S. Bohlmann J. Covello P. S. De Luca V. Page J. E. Ro D. K. Martin V. JJ. Facchini P. J. Sensen C. W. Transcriptome analysis based on next-generation sequencing of non-model plants producing specialized metabolites of biotechnological interest. J Biotechnol: 2013; 166 122 134
84. Verma M. Ghangal R. Sharma R. Sinha A. K. Jain M. Transcriptome analysis of Catharanthus roseus for gene discovery and expression profiling. PLoS One: 2014; 9 e103583
85. de Bernonville T. D. Foureau E. Parage C. Lanoue A. Clastre M. Londono M. A. Oudin A. Houille B. Papon N. Besseau S. Glevarec G. Atehortua L. Giglioli-Guivarc'h N. St-Pierre B. De Luca V. O'Connor S. E. Courdavault V. Characterization of a second secologanin synthase isoform producing both secologanin and secoxyloganin allows enhanced de novo assembly of a Catharanthus roseus transcriptome. BMC Genomics: 2015; 16 619
86. Giddings L. A. Liscombe D. K. Hamilton J. P. Childs K. L. DellaPenna D. Buell C. R. O'Connor S. E. A stereoselective hydroxylation step of alkaloid biosynthesis by a unique cytochrome P450 in Catharanthus roseus. J Biol Chem: 2011; 286 16751 16757
87. Guirimand G. Courdavault V. Lanoue A. Mahroug S. Guihur A. Blanc N. Giglioli-Guivarc'h N. St-Pierre B. Burlat V. Strictosidine activation in Apocynaceae: towards a nuclear time bomb? BMC Plant Biol: 2010; 10 182
88. Yu F. De Luca V. ATP-binding cassette transporter controls leaf surface secretion of anticancer drug components in Catharanthus roseus. Proc Natl Acad Sci U S A: 2013; 110 15830 15835
89. Carqueijeiro I. Noronha H. Duarte P. Geros H. Sottomayor M. Vacuolar transport of the medicinal alkaloids from Catharanthus roseus is mediated by a proton-driven antiport. Plant Physiol: 2013; 162 1486 1496
90. Payne R. ME. Xu D. Y. Foureau E. Teto Carqueijeiro M. I. Oudin A. de Bernonville T. D. Novak V. Burow M. Olsen C. E. Jones D. M. Tatsis E. C. Pendle A. Halkier B. A. Geu-Flores F. Courdavault V. Nour-Eldin H. H. O'Connor S. E. An NPF transporter exports a central monoterpene indole alkaloid intermediate from the vacuole. Nat Plants: 2017; 3 16208
91. Brown S. Clastre M. Courdavault V. O'Connor S. E. De novo production of the plant-derived alkaloid strictosidine in yeast. Proc Natl Acad Sci U S A: 2015; 112 3205 3210
92. Kennedy J. Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products. Nat Prod Rep: 2008; 25 25 34
93. Mechoulam R. Hanus L. O. Pertwee R. Howlett A. C. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci: 2014; 15 757 764
94. Owens B. Drug development: the treasure chest. Nature: 2015; 525 S6
95. Pain S. A potted history. Nature: 2015; 525 S10
96. Andre C. M. Hausman J. F. Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci: 2016; 7 19
97. Grotenhermen F. Muller-Vahl K. Medicinal uses of marijuana and cannabinoids. Crit Rev Plant Sci: 2016; 35 378 405
98. Todd A. R. Hashish. Experientia: 1946; 2 55 60
99. Mechoulam R. Shvo Y. Hashish. 1. Structure of cannabidiol. Tetrahedron: 1963; 19 2073 2078
100. Gaoni Y. Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc: 1964; 86 1646 1647
101. Devane W. A. Dysarz F. A. Johnson M. R. Melvin L. S. Howlett A. C. Determination and characterization of a cannabinoid receptor in rat-brain. Mol Pharmacol: 1988; 34 605 613
102. Matsuda L. A. Lolait S. J. Brownstein M. J. Young A. C. Bonner T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature: 1990; 346 561 564
103. Munro S. Thomas K. L. Abushaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature: 1993; 365 61 65
104. Devane W. A. Hanus L. Breuer A. Pertwee R. G. Stevenson L. A. Griffin G. Gibson D. Mandelbaum A. Etinger A. Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science: 1992; 258 1946 1949
105. Russo E. B. Beyond cannabis: plants and the endocannabinoid system. Trends Pharmacol Sci: 2016; 37 594 605
106. van Bakel H. Stout J. M. Cote A. G. Tallon C. M. Sharpe A. G. Hughes T. R. Page J. E. The draft genome and transcriptome of Cannabis sativa. Genome Biol: 2011; 12 R102
107. Gagne S. J. Stout J. M. Liu E. W. Boubakir Z. Clark S. M. Page J. E. Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides. Proc Natl Acad Sci U S A: 2012; 109 12811 12816
108. Stout J. M. Boubakir Z. Ambrose S. J. Purves R. W. Page J. E. The hexanoyl-CoA precursor for cannabinoid biosynthesis is formed by an acyl-activating enzyme in Cannabis sativa trichomes. Plant J: 2012; 71 353 365
109. Kajima M. Piraux M. The biogenesis of cannabinoids in Cannabis sativa. Phytochemistry: 1982; 21 67 69
110. Fellermeier M. Eisenreich W. Bacher A. Zenk M. H. Biosynthesis of cannabinoids - incorporation experiments with C-13-labeled glucoses. Eur J Biochem: 2001; 268 1596 1604
111. Fellermeier M. Zenk M. H. Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol. FEBS Lett: 1998; 427 283 285
112. Page J. E. Boubakir Z. Aromatic prenyltransferase from cannabis. US National Research Council of Canada, University of Saskatchewan. US patent US20150128301 A1: 2014
113. Sirikantaramas S. Taura F. Cannabinoids: Biosynthesis and biotechnological Applications. In: Chandra S. Lata H. ElSohly M. A. eds. Cannabis sativa L. - Botany and Biotechnology. Cham Springer International Publishing: 2017; 183 206
114. Weiblen G. D. Wenger J. P. Craft K. J. ElSohly M. A. Mehmedic Z. Treiber E. L. Marks M. D. Gene duplication and divergence affecting drug content in Cannabis sativa. New Phytol: 2015; 208 1241 1250
115. Sirikantaramas S. Morimoto S. Shoyama Y. Ishikawa Y. Wada Y. Shoyama Y. Taura F. The gene controlling marijuana psychoactivity - molecular cloning and heterologous expression of delta(1)-tetrahydrocannabinolic acid synthase from Cannabis sativa L. J Biol Chem: 2004; 279 39767 39774
116. Taura F. Morimoto S. Shoyama Y. Purification and characterization of cannabidiolic-acid synthase from Cannabis sativa L. Biochemical analysis of a novel enzyme that catalyzes the oxidocyclization of cannabigerolic acid to cannabidiolic acid. J Biol Chem: 1996; 271 17411 17416
117. Taura F. Sirikantaramas S. Shoyama Y. Yoshikai K. Shoyama Y. Morimoto S. Cannabidiolic-acid synthase, the chemotype-determining enzyme in the fiber-type Cannabis sativa. FEBS Lett: 2007; 581 2929 2934
118. Shimizu Y. Ogata H. Goto S. Type III polyketide synthases: functional classification and phylogenomics. Chembiochem: 2017; 18 50 65
119. Marks M. D. Tian L. Wenger J. P. Omburo S. N. Soto-Fuentes W. He J. Gang D. R. Weiblen G. D. Dixon R. A. Identification of candidate genes affecting delta(9)-tetrahydrocannabinol biosynthesis in Cannabis sativa. J Exp Bot: 2009; 60 3715 3726
120. Taura F. Tanaka S. Taguchi C. Fukamizu T. Tanaka H. Shoyama Y. Morimoto S. Characterization of olivetol synthase, a polyketide synthase putatively involved in cannabinoid biosynthetic pathway. FEBS Lett: 2009; 583 2061 2066
121. Shen Y. M. Yoon P. Yu T. W. Floss H. G. Hopwood D. Moore B. S. Ectopic expression of the minimal whiE polyketide synthase generates a library of aromatic polyketides of diverse sizes and shapes. Proc Natl Acad Sci U S A: 1999; 96 3622 3627
122. MacCallum C. A. Russo E. B. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med: 2018; 49 12 19
123. Burstein S. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorgan Med Chem: 2015; 23 1377 1385
124. Flores-Sanchez I. J. Pec J. Fei J. N. Choi Y. H. Dusek J. Verpoorte R. Elicitation studies in cell suspension cultures of Cannabis sativa L. J Biotechnol: 2009; 143 157 168
125. Farag S. Kayser O. Cannabinoids production by hairy root cultures of Cannabis sativa L. Am J Plant Sci: 2015; 6 1874 1884
126. Lange K. Schmid A. Julsing M. K. Delta(9)-tetrahydrocannabinolic acid synthase production in Pichia pastoris enables chemical synthesis of cannabinoids. J Biotechnol: 2015; 211 68 76
127. Lange K. Schmid A. Julsing M. K. Delta 9-tetrahydrocannabinolic acid synthase: the application of a plant secondary metabolite enzyme in biocatalytic chemical synthesis. J Biotechnol: 2016; 233 42 48
128. Denoeud F. Carretero-Paulet L. Dereeper A. Droc G. Guyot R. Pietrella M. Zheng C. F. Alberti A. Anthony F. Aprea G. Aury J. M. Bento P. Bernard M. Bocs S. Campa C. Cenci A. Combes M. C. Crouzillat D. Da Silva C. Daddiego L. De Bellis F. Dussert S. Garsmeur O. Gayraud T. Guignon V. Jahn K. Jamilloux V. Joet T. Labadie K. Lan T. Y. Leclercq J. Lepelley M. Leroy T. Li L. T. Librado P. Lopez L. Munoz A. Noel B. Pallavicini A. Perrotta G. Poncet V. Pot D. Priyono Rigoreau M. Rouard M. Rozas J. Tranchant-Dubreuil C. VanBuren R. Zhang Q. Andrade A. C. Argout X. Bertrand B. de Kochko A. Graziosi G. Henry R. J. Jayarama Ming R. Nagai C. Rounsley S. Sankoff D. Giuliano G. Albert V. A. Wincker P. Lashermes P. The coffee genome provides insight into the convergent evolution of caffeine biosynthesis. Science: 2014; 345 1181 1184
129. Xia E. H. Zhang H. B. Sheng J. Li K. Zhang Q. J. Kim C. Zhang Y. Liu Y. Zhu T. Li W. Huang H. Tong Y. Nan H. Shi C. Shi C. Jiang J. J. Mao S. Y. Jiao J. Y. Zhang D. Zhao Y. Zhao Y. J. Zhang L. P. Liu Y. L. Liu B. Y. Yu Y. Shao S. F. Ni D. J. Eichler E. E. Gao L. Z. The tea tree genome provides insights into tea flavor and independent evolution of caffeine biosynthesis. Mol Plant: 2017; 10 866 877
130. Argout X. Salse J. Aury J. M. Guiltinan M. J. Droc G. Gouzy J. Allegre M. Chaparro C. Legavre T. Maximova S. N. Abrouk M. Murat F. Fouet O. Poulain J. Ruiz M. Roguet Y. Rodier-Goud M. Barbosa-Neto J. F. Sabot F. Kudrna D. Ammiraju J. SS. Schuster S. C. Carlson J. E. Sallet E. Schiex T. Dievart A. Kramer M. Gelley L. Shi Z. Berard A. Viot C. Boccara M. Risterucci A. M. Guignon V. Sabau X. Axtell M. J. Ma Z. R. Zhang Y. F. Brown S. Bourge M. Golser W. Song X. A. Clement D. Rivallan R. Tahi M. Akaza J. M. Pitollat B. Gramacho K. D'Hont A. Brunel D. Infante D. Kebe I. Costet P. Wing R. McCombie W. R. Guiderdoni E. Quetier F. Panaud O. Wincker P. Bocs S. Lanaud C. The genome of Theobroma cacao. Nat Genet: 2011; 43 101 108
131. Frischknecht P. M. Baumann T. W. Stress-induced formation of purine alkaloids in plant-tissue culture of Coffea arabica. Phytochemistry: 1985; 24 2255 2257
132. Hollingsworth R. G. Armstrong J. W. Campbell E. Pest control: caffeine as a repellent for slugs and snails. Nature: 2002; 417 915 916
133. Uefuji H. Tatsumi Y. Morimoto M. Kaothien-Nakayama P. Ogita S. Sano H. Caffeine production in tobacco plants by simultaneous expression of three coffee N-methyltrasferases and its potential as a pest repellant. Plant Mol Biol: 2005; 59 221 227
134. Friedman J. Waller G. R. Caffeine hazards and their prevention in germinating-seeds of coffee (Coffea arabica L). J Chem Ecol: 1983; 9 1099 1106
135. Wang L. Nagele T. Doerfler H. Fragner L. Chaturvedi P. Nukarinen E. Bellaire A. Huber W. Weiszmann J. Engelmeier D. Ramsak Z. Gruden K. Weckwerth W. System level analysis of cacao seed ripening reveals a sequential interplay of primary and secondary metabolism leading to polyphenol accumulation and preparation of stress resistance. Plant J: 2016; 87 318 332
136. García-Flores M. Juárez-Colunga S. García-Casarrubias A. Trachsel S. Winkler R. Tiessen A. Metabolic profiling of plant extracts using direct-injection electrospray ionization mass spectrometry allows for high-throughput phenotypic characterization according to genetic and environmental effects. J Agric Food Chem: 2015; 63 1042 1052
137. Chang K. L. Ho P. C. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics for comparison of caffeinated and decaffeinated coffee and its implications for Alzheimer's disease. PLoS One: 2014; 9 e104621
138. Wei F. Furihata K. Koda M. Hu F. Miyakawa T. Tanokura M. Roasting process of coffee beans as studied by nuclear magnetic resonance: time course of changes in composition. J Agric Food Chem: 2012; 60 1005 1012
139. Kellogg J. J. Wallace E. D. Graf T. N. Oberlies N. H. Cech N. B. Conventional and accelerated-solvent extractions of green tea (Camellia sinensis) for metabolomics-based chemometrics. J Pharmaceut Biomed: 2017; 145 604 610
140. Li P. Dai W. Lu M. Xie D. Tan J. Yang C. Zhu Y. Lv H. Peng Q. Zhang Y. Guo L. Ni D. Lin Z. Metabolomic analysis reveals the composition differences in 13 Chinese tea cultivars of different manufacturing suitabilities. J Sci Food Agric: 2018; 98 1153 1161
141. Kellogg J. J. Graf T. N. Paine M. F. McCune J. S. Kvalheim O. M. Oberlies N. H. Cech N. B. Comparison of metabolomics approaches for evaluating the variability of complex botanical preparations: green tea (Camellia sinensis) as a case study. J Nat Prod: 2017; 80 1457 1466
142. Cheng B. Furtado A. Henry R. J. Long-read sequencing of the coffee bean transcriptome reveals the diversity of full-length transcripts. Gigascience: 2017; 6 1 13
143. Zhang Q. F. Liu M. Y. Ruan J. Y. Integrated transcriptome and metabolic analyses reveals novel insights into free amino acid metabolism in Huangjinya tea cultivar. Front Plant Sci: 2017; 8 291
144. Mukhopadhyay M. Mondal T. K. Chand P. K. Biotechnological advances in tea (Camellia sinensis [L.] O. Kuntze): a review. Plant Cell Rep: 2016; 35 255 287
145. da Hora Junior B. T. Poloni Jde F. Lopes M. A. Dias C. V. Gramacho K. P. Schuster I. Sabau X. Cascardo J. C. Mauro S. M. Gesteira Ada S. Bonatto D. Micheli F. Transcriptomics and systems biology analysis in identification of specific pathways involved in cacao resistance and susceptibility to witches' broom disease. Mol Biosyst: 2012; 8 1507 1519
146. Dereeper A. Bocs S. Rouard M. Guignon V. Ravel S. Tranchant-Dubreuil C. Poncet V. Garsmeur O. Lashermes P. Droc G. The coffee genome hub: a resource for coffee genomes. Nucleic Acids Res: 2015; 43 D1028 D1035
147. Campos N. A. Panis B. Carpentier S. C. Somatic embryogenesis in coffee: the evolution of biotechnology and the integration of omics technologies offer great opportunities. Front Plant Sci: 2017; 8 1460
148. Weinreb O. Amit T. Youdim M. BH. A novel approach of proteomics and transcriptomics to study the mechanism of action of the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin-3-gallate. Free Radic Biol Med: 2007; 43 546 556
149. Li C. F. Zhu Y. Yu Y. Zhao Q. Y. Wang S. J. Wang X. C. Yao M. Z. Luo D. Li X. Chen L. Yang Y. J. Global transcriptome and gene regulation network for secondary metabolite biosynthesis of tea plant (Camellia sinensis). BMC Genomics: 2015; 16 560
150. Tai Y. Wei C. Yang H. Zhang L. Chen Q. Deng W. Wei S. Zhang J. Fang C. Ho C. Wan X. Transcriptomic and phytochemical analysis of the biosynthesis of characteristic constituents in tea (Camellia sinensis) compared with oil tea (Camellia oleifera). BMC Plant Biol: 2015; 15 190
151. Taylor A. E. Davey Smith G. Munafò M. R. Associations of coffee genetic risk scores with consumption of coffee, tea and other beverages in the UK Biobank. Addiction: 2018; 113 148 157
152. James J. E. Stirling K. P. Caffeine - a survey of some of the known and suspected deleterious effects of habitual use. Brit J Addict: 1983; 78 251 258
153. Program B. CDS. Coffee drinking and acute myocardial infarction. Lancet: 1972; 300 1278 1281
154. Jick H. Miettinen O. S. Neff R. K. Shapiro S. Heinonen O. P. Slone D. Coffee and myocardial-infarction. N Engl J Med: 1973; 289 63 67
155. Freedman N. D. Park Y. Abnet C. C. Hollenbeck A. R. Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med: 2012; 366 1891 1904
156. Alicandro G. Tavani A. La Vecchia C. Coffee and cancer risk: a summary overview. Eur J Cancer Prev: 2017; 26 424 432
157. Ahmed I. Lee P. C. Lill C. M. Nielsen S. S. Artaud F. Gallagher L. G. Loriot M. A. Mulot C. Nacfer M. Liu T. Biernacka J. M. Armasu S. Anderson K. Farin F. M. Lassen C. F. Hansen J. Olsen J. H. Bertram L. Maraganore D. M. Checkoway H. Ritz B. Elbaz A. Lack of replication of the GRIN2A-by-coffee interaction in Parkinson disease. PLoS Genet: 2014; 10 e1004788
158. Tanida I. Shirasago Y. Suzuki R. Abe R. Wakita T. Hanada K. Fukasawa M. Inhibitory effects of caffeic acid, a coffee-related organic acid, on the propagation of hepatitis C virus. Jpn J Infect Dis: 2015; 68 268 275
159. Platt D. E. Ghassibe-Sabbagh M. Salameh P. Salloum A. K. Haber M. Mouzaya F. Gauguier D. Al-Sarraj Y. El-Shanti H. Zalloua P. A. Abchee A. B. Caffeine impact on metabolic syndrome components is modulated by a CYP1A2 variant. Ann Nutr Metab: 2016; 68 1 11
160. Jaquet M. Rochat I. Moulin J. Cavin C. Bibiloni R. Impact of coffee consumption on the gut microbiota: a human volunteer study. Int J Food Microbiol: 2009; 130 117 121
161. Crocq M. A. Alcohol, nicotine, caffeine, and mental disorders. Dialogues Clin Neurosci: 2003; 5 175 185
162. Nag S. A. Qin J. J. Wang W. Wang M. H. Wang H. Zhang R. W. Ginsenosides as anticancer agents: in vitro and in vivo activities, structure-activity relationships, and molecular mechanisms of action. Front Pharmacol: 2012; 3 25
163. Hemmerly T. E. Ginseng farm in Lawrence-County, Tennessee. Econ Bot: 1977; 31 160 162
164. Oh J. Y. Kim Y. J. Jang M. G. Joo S. C. Kwon W. S. Kim S. Y. Jung S. K. Yang D. C. Investigation of ginsenosides in different tissues after elicitor treatment in Panax ginseng. J Ginseng Res: 2014; 38 270 277
165. Christensen L. P. Ginsenosides: Chemistry, Biosynthesis, Analysis, and potential Health Effects. In: Taylor S. ed. Advances in Food and Nutrition Research, vol. 55. Cambridge Academic Press: 2008; 1 99
166. Wang C. Z. Aung H. H. Ni M. Wu J. A. Tong R. B. Wicks S. He T. C. Yuan C. S. Red American ginseng: ginsenoside constituents and antiproliferative activities of heat-processed Panax quinquefolius roots. Planta Med: 2007; 73 669 674
167. Yue P. YK. Wong D. YL. Wu P. K. Leung P. Y. Mak N. K. Yeung H. W. Liu L. Cai Z. Jiang Z. H. Fan T. PD. Wong R. NS. The angiosuppressive effects of 20(R)- ginsenoside Rg3. Biochem Pharmacol: 2006; 72 437 445
168. Yu Y. Zhou Q. Hang Y. Bu X. Jia W. Antiestrogenic effect of 20S-protopanaxadiol and its synergy with tamoxifen on breast cancer cells. Cancer: 2007; 109 2374 2382
169. Wang W. Zhao Y. Rayburn E. R. Hill D. L. Wang H. Zhang R. In vitro anti-cancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng. Cancer Chemother Pharmacol: 2007; 59 589 601
170. Wang W. Rayburn E. R. Hao M. Zhao Y. Hill D. L. Zhang R. W. Wang H. Experimental therapy of prostate cancer with novel natural product anti-cancer ginsenosides. Prostate: 2008; 68 809 819
171. Wang W. Wang H. Rayburn E. R. Zhao Y. Hill D. L. Zhang R. 20(S)-25-methoxyl-dammarane-3 beta,12 beta,20-triol, a novel natural product for prostate cancer therapy: activity in vitro and in vivo and mechanisms of action. Br J Cancer: 2008; 98 792 802
172. Wang W. Rayburn E. R. Hang J. Zhao Y. Wang H. Zhang R. Anti-lung cancer effects of novel ginsenoside 25-OCH3-PPD. Lung Cancer: 2009; 65 306 311
173. Kang K. S. Kim H. Y. Yamabe N. Yokozawa T. Stereospecificity in hydroxyl radical scavenging activities of four ginsenosides produced by heat processing. Bioorg Med Chem Lett: 2006; 16 5028 5031
174. Schramek N. Huber C. Schmidt S. Dvorski S. EM. Knispel N. Ostrozhenkova E. Pena-Rodriguez L. M. Cusido R. M. Wischmann G. Eisenreich W. Biosynthesis of ginsenosides in field-grown Panax ginseng. JSM Biotechnol Bioeng: 2014; 2 1033
175. Zhao S. Wang L. Liu L. Liang Y. Sun Y. Wu J. Both the mevalonate and the non-mevalonate pathways are involved in ginsenoside biosynthesis. Plant Cell Rep: 2014; 33 393 400
176. Wang J. Gao W. Y. Zhang J. Zuo B. M. Zhang L. M. Huang L. Q. Advances in study of ginsenoside biosynthesis pathway in Panax ginseng C.A. Meyer. Acta Physiol Plant: 2012; 34 397 403
177. Xu R. Fazio G. C. Matsuda S. PT. On the origins of triterpenoid skeletal diversity. Phytochemistry: 2004; 65 261 291
178. Wang L. Zhao S. J. Cao H. J. Sun Y. The isolation and characterization of dammarenediol synthase gene from Panax quinquefolius and its heterologous co-expression with cytochrome P450 gene PqD12H in yeast. Funct Integr Genomics: 2014; 14 545 557
179. Hu W. Liu N. Tian Y. Zhang L. Molecular cloning, expression, purification, and functional characterization of dammarenediol synthase from Panax ginseng. Biomed Res Int: 2013; 2013 7
180. Jung S. C. Kim W. Park S. C. Jeong J. Park M. K. Lim S. Lee Y. Im W. T. Lee J. H. Choi G. Kim S. C. Two ginseng UDP-glycosyltransferases synthesize ginsenoside Rg(3) and Rd. Plant Cell Physiol: 2014; 55 2177 2188
181. Wei W. Wang P. P. Wei Y. J. Liu Q. F. Yang C. S. Zhao G. P. Yue J. M. Yan X. Zhou Z. H. Characterization of Panax ginseng UDP-glycosyltransferases catalyzing protopanaxatriol and biosyntheses of bioactive ginsenosides F1 and Rh1 in metabolically engineered yeasts. Mol Plant: 2015; 8 1412 1424
182. Hasegawa H. Proof of the mysterious efficacy of ginseng: basic and clinical trials: metabolic activation of ginsenoside: deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci: 2004; 95 153 157
183. Zheng Z. Z. Ming Y. L. Chen L. H. Zheng G. H. Liu S. S. Chen Q. X. Compound K-induced apoptosis of human hepatocellular carcinoma MHCC97-H cells in vitro. Oncol Rep: 2014; 32 325 331
184. Lee S. Kwon M. C. Jang J. P. Sohng J. K. Jung H. J. The ginsenoside metabolite compound K inhibits growth, migration and sternness of glioblastoma cells. Int J Oncol: 2017; 51 414 424
185. Yan X. Fan Y. Wei W. Wang P. P. Liu Q. F. Wei Y. J. Zhang L. Zhao G. P. Yue J. M. Zhou Z. H. Production of bioactive ginsenoside compound K in metabolically engineered yeast. Cell Res: 2014; 24 770 773
186. Wu J. Y. Zhong J. J. Production of ginseng and its bioactive components in plant cell culture: current technological and applied aspects. J Biotechnol: 1999; 68 89 99
187. Baque M. A. Moh S. H. Lee E. J. Zhong J. J. Paek K. Y. Production of biomass and useful compounds from adventitious roots of high-value added medicinal plants using bioreactor. Biotechnol Adv: 2012; 30 1255 1267
188. Lee M. H. Jeong J. H. Seo J. W. Shin C. G. Kim Y. S. In J. G. Yang D. C. Yi J. S. Choi Y. E. Enhanced triterpene and phytosterol biosynthesis in Panax ginseng overexpressing squalene synthase gene. Plant Cell Physiol: 2004; 45 976 984
189. Sivakumar G. Yu K. W. Paek K. Y. Biosafe ginseng: a novel source for human well-being. Eng Life Sci: 2005; 5 527 533
190. Luo S. Callus culture of Panax ginseng. Plant Physiol Commun: 1964; 2 26 38
191. Furuya T. Yoshikawa T. Orihara Y. Oda H. Studies on plant-tissue cultures. 39. Saponin production in cell-suspension cultures of Panax ginseng. Planta Med: 1983; 48 83 87
192. Inomata S. Yokoyama M. Gozu Y. Shimizu T. Yanagi M. Growth-pattern and ginsenoside production of agrobacterium-transformed Panax ginseng roots. Plant Cell Rep: 1993; 12 681 686
193. Choi K. T. Ahn I. O. Park J. C. Production of ginseng saponin in tissue-culture of ginseng (Panax ginseng Ca Meyer). Russ J Plant Physl: 1994; 41 784 788
194. Zhang Y. H. Zhong J. J. Yu J. Y. Enhancement of ginseng saponin production in suspension cultures of Panax notoginseng: manipulation of medium sucrose. J Biotechnol: 1996; 51 49 56
195. Zhong J. J. Zhu Q. X. Effect of initial phosphate concentration on cell growth and ginsenoside saponin production by suspended cultures of Panax notoginseng. Biotechnol Appl Biochem: 1995; 55 241 247
196. Paek K. Y. Murthy H. N. Hahn E. J. Zhong J. J. Large Scale Culture of Ginseng adventitious Roots for Production of Ginsenosides. In: Zhong J. J. Bai F. W. Zhang W. eds. Biotechnology in China I: From Bioreaction to Bioseparation and Bioremediation. Berlin, Heidelberg Springer: 2009; 151 176
197. Gao X. Zhu C. Jia W. Gao W. Qiu M. Zhang Y. Xiao P. Induction and characterization of adventitious roots directly from the explants of Panax notoginseng. Biotechnol Lett: 2005; 27 1771 1775
198. Osbourn A. E. Preformed antimicrobial compounds and plant defense against fungal attack. Plant Cell: 1996; 8 1821 1831
199. Augustin J. M. Kuzina V. Andersen S. B. Bak S. Molecular activities, biosynthesis and evolution of triterpenoid saponins. Phytochemistry: 2011; 72 435 457
200. Ali M. B. Yu K. W. Hahn E. J. Paek K. Y. Methyl jasmonate and salicylic acid elicitation induces ginsenosides accumulation, enzymatic and non-enzymatic antioxidant in suspension culture Panax ginseng roots in bioreactors. Plant Cell Rep: 2006; 25 613 620
201. Kim D. S. Song M. Kim S. H. Jang D. S. Kim J. B. Ha B. K. Kim S. H. Lee K. J. Kang S. Y. Jeong I. Y. The improvement of ginsenoside accumulation in Panax ginseng as a result of gamma-irradiation. J Ginseng Res: 2013; 37 332 340
202. Kim Y. J. Lee O. R. Oh J. Y. Jang M. G. Yang D. C. Functional analysis of 3-hydroxy-3-methylglutaryl coenzyme a reductase encoding genes in triterpene saponin-producing ginseng. Plant Physiol: 2014; 165 373 387
203. Han J. Y. Kim H. J. Kwon Y. S. Choi Y. E. The Cyt P450 enzyme CYP716A47 catalyzes the formation of protopanaxadiol from dammarenediol-II during ginsenoside biosynthesis in Panax ginseng. Plant Cell Physiol: 2011; 52 2062 2073
204. Han J. Y. Kwon Y. S. Yang D. C. Jung Y. R. Choi Y. E. Expression and RNA interference-induced silencing of the dammarenediol synthase gene in Panax ginseng. Plant Cell Physiol: 2006; 47 1653 1662
205. Dai Z. Wang B. Liu Y. Shi M. Wang D. Zhang X. Liu T. Huang L. Zhang X. Producing aglycons of ginsenosides in bakers' yeast. Sci Rep: 2014; 4 3698
206. Mirjalili M. H. Moyano E. Bonfill M. Cusido R. M. Palazon J. Steroidal lactones from Withania somnifera, an ancient plant for novel medicine. Molecules: 2009; 14 2373 2393
207. Dar N. J. Hamid A. Ahmad M. Pharmacologic overview of Withania somnifera, the Indian ginseng. Cell Mol Life Sci: 2015; 72 4445 4460
208. Rai M. Jogee P. S. Agarkar G. dos Santos C. A. Anticancer activities of Withania somnifera: current research, formulations, and future perspectives. Pharm Biol: 2016; 54 189 197
209. Falkenberg K. D. Jakobs A. Matern J. C. Dörner W. Uttarkar S. Trentmann A. Steinmann S. Coulibaly A. Schomburg C. Mootz H. D. Schmidt T. J. Klempnauer K. H. Withaferin A, a natural compound with anti-tumor activity, is a potent inhibitor of transcription factor C/EBP β Biochim Biophys Acta: 2017; 1864 1349 1358
210. Mohan R. Hammers H. Bargagna-Mohan P. Zhan X. Herbstritt C. Ruiz A. Zhang L. Hanson A. Conner B. Rougas J. Pribluda V. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis: 2004; 7 115 122
211. ∗,1 J Org Chem: 1965; 30 1774 1778
212. Bhat W. W. Lattoo S. K. Razda S. Dhar N. Rana S. Dhar R. S. Khan S. Vishwakarma R. A. Molecular cloning, bacterial expression and promoter analysis of squalene synthase from Withania somnifera (L.) Dunal. Gene: 2012; 499 25 36
213. Razdan S. Bhat W. W. Rana S. Dhar N. Lattoo S. K. Dhar R. S. Vishwakarma R. A. Molecular characterization and promoter analysis of squalene epoxidase gene from Withania somnifera (L.) Dunal. Mol Biol Rep: 2013; 40 905 916
214. Senthil K. Wasnik N. G. Kim Y. J. Yang D. C. Generation and analysis of expressed sequence tags from leaf and root of Withania somnifera (Ashwgandha). Mol Biol Rep: 2010; 37 893 902
215. Dhar N. Rana S. Bhat W. W. Razdan S. Pandith S. A. Khan S. Dutt P. Dhar R. S. Vaishnavi S. Vishwakarma R. Lattoo S. K. Dynamics of withanolide biosynthesis in relation to temporal expression pattern of metabolic genes in Withania somnifera (L.) Dunal: a comparative study in two morpho-chemovariants. Mol Biol Rep: 2013; 40 7007 7016
216. Sabir F. Mishra S. Sangwan R. S. Jadaun J. S. Sangwan N. S. Qualitative and quantitative variations in withanolides and expression of some pathway genes during different stages of morphogenesis in Withania somnifera Dunal. Protoplasma: 2013; 250 539 549
217. Chen L. X. He H. Qiu F. Natural withanolides: an overview. Nat Prod Rep: 2011; 28 705 740
218. Rana S. Lattoo S. K. Dhar N. Razdan S. Bhat W. W. Dhar R. S. Vishwakarma R. NADPH-cytochrome P450 reductase: molecular cloning and functional characterization of two paralogs from Withania somnifera (L.) Dunal. PLoS One: 2013; 8 e57068
219. Mishra S. Bansal S. Mishra B. Sangwan R. S. Jadaun A. JS. Sangwan N. S. RNAi and homologous over-expression based functional approaches reveal triterpenoid synthase gene-cycloartenol synthase is involved in downstream withanolide biosynthesis in Withania somnifera. PLoS One: 2016; 11 e0149691
220. Agarwal A. V. Gupta P. Singh D. Dhar Y. V. Chandra D. Trivedi P. K. Comprehensive assessment of the genes involved in withanolide biosynthesis from Withania somnifera: chemotype-specific and elicitor-responsive expression. Funct Integr Genomics: 2017; 17 477 490
221. Agarwal A. V. Singh D. Dhar Y. V. Michael R. Gupta P. Chandra D. Trivedi P. K. Virus-induced silencing of key genes leads to differential impact on withanolide biosynthesis in the medicinal plant, Withania somnifera. Plant Cell Physiol: 2018; 59 262 274
222. Singh N. Bhalla M. de Jager P. Gilca M. An overview on ashwagandha: a Rasayana (rejuvenator) of Ayurveda. Afr J Tradit Complement Altern Med: 2011; 8 208 213
223. Ghosal S. Lal J. Srivastava R. Bhattacharya S. K. Upadhyay S. N. Jaiswal A. K. Chattopadhyay U. Immunomodulatory and CNS effects of sitoindosides IX and X, two new glycowithanolides from Withania somnifera. Phytother Res: 1989; 3 201 206
224. Chengappa K. N. Bowie C. Schlicht P. J. Fleet D. Brar J. S. Jindal R. Randomized placebo-controlled adjunctive study of an extract of Withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry: 2013; 74 1076 1083
225. Choudhary D. Bhattacharyya S. Bose S. Efficacy and safety of ashwagandha (Withania somnifera (L.) Dunal) root extract in improving memory and cognitive functions. J Diet Suppl: 2017; 14 599 612
226. Dhuley J. N. Effect of ashwagandha on lipid peroxidation in stress-induced animals. Ethnopharmacol: 1998; 60 173 178
227. Durg S. Dhadde S. B. Vandal R. Shivakumar B. S. Charan C. S. Withania somnifera (Ashwagandha) in neurobehavioural disorders induced by brain oxidative stress in rodents: a systematic review and meta-analysis. J Pharm Pharmacol: 2015; 67 879 899
228. Sehgal N. Gupta A. Valli R. K. Joshi S. D. Mills J. T. Hamel E. Khanna P. Jain S. C. Thakur S. S. Ravindranath V. Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci U S A: 2012; 109 3510 3515
229. Ahmad M. Saleem S. Ahmad A. S. Ansari M. A. Yousuf S. Hoda M. N. Islam F. Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats. Hum Exp Toxicol: 2005; 24 137 147
230. Devi P. U. Akagi K. Ostapenko V. Tanaka Y. Sugahara T. Withaferin A: A new radiosensitizer from the Indian medicinal plant Withania somnifera. Int J Radiat Biol: 1996; 69 193 197
231. Prakash J. Gupta S. K. Dinda A. K. Withania somnifera root extract prevents DMBA-induced squamous cell carcinoma of skin in Swiss albino mice. Nutr Cancer: 2002; 42 91 97
232. Stan S. D. Hahm E. R. Warin R. Singh S. V. Withaferin A causes FOXO3a- and bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res: 2008; 68 7661 7669
233. Ghosh K. De S. Mukherjee S. Das S. Ghosh A. N. Sengupta S. Withaferin A induced impaired autophagy and unfolded protein response in human breast cancer cell-lines MCF-7 and MDA-MB-231. Toxicol In Vitro: 2017; 44 330 338
234. Hsieh P. W. Huang Z. Y. Chen J. H. Chang F. R. Wu C. C. Yang Y. L. Chiang M. Y. Yen M. H. Chen S. L. Yen H. F. Lübken T. Hung W. C. Wu Y. C. Cytotoxic withanolides from Tubocapsicum anomalum. J Nat Prod: 2007; 70 747 753
235. Abdeljebbar L. H. Benjouad A. Morjani H. Merghoub N. El Haddar S. Humam M. Christen P. Hostettmann K. Bekkouche K. Amzazi S. Antiproliferative effects of withanolides from Withania adpressa. Therapie: 2009; 64 121 127
236. Lee S. W. Pan M. H. Chen C. M. Chen Z. T. Withangulatin I, a new cytotoxic withanolide from Physalis angulata. Chem Pharm Bull (Tokyo): 2008; 56 234 236
237. Biswal B. M. Sulaiman A. M. Ismail H. C. Zakaria H. Jalil Abdul M. I. Muhammad K. I. AOS14 Phase II clinical study of combination chemotherapy with herb Withania somnifera (ashwagandha) in breast cancer. Eur J Cancer: 2012; 48 S8 S9
238. Biswal B. M. Sulaiman S. A. Ismail H. C. Zakaria H. Musa K. I. Effect of Withania somnifera (ashwagandha) on the development of chemotherapy-induced fatigue and quality of life in breast cancer patients. Integr Cancer Ther: 2013; 12 312 322
239. Ho W. E. Peh H. Y. Chan T. K. Wong W. SF. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther: 2014; 142 126 139
240. Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med: 2011; 17 1217
241. White N. J. Qinghaosu (artemisinin): the price of success. Science: 2008; 320 330
242. Nosten F. White N. J. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg: 2007; 77 181 192
243. World Health Organization Global Health Observatory. Available at: http://www.who.int/gho/malaria/en/ Accessed May 23, 2018
244. Banek K. Lalani M. Staedke S. G. Chandramohan D. Adherence to artemisinin-based combination therapy for the treatment of malaria: a systematic review of the evidence. Malar J: 2014; 13 7
245. Lalloo D. G. Shingadia D. Bell D. J. Beeching N. J. Whitty C. JM. Chiodini P. L. UK malaria treatment guidelines 2016. J Infect: 2016; 72 635 649
246. Straimer J. Gnädig N. F. Witkowski B. Amaratunga C. Duru V. Ramadani A. P. Dacheux M. Khim N. Zhang L. Lam S. Gregory P. D. Urnov F. D. Mercereau-Puijalon O. Benoit-Vical F. Fairhurst R. M. Ménard D. Fidock D. A. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science: 2015; 347 428
247. Mbengue A. Bhattacharjee S. Pandharkar T. Liu H. Estiu G. Stahelin R. V. Rizk S. S. Njimoh D. L. Ryan Y. Chotivanich K. Nguon C. Ghorbal M. Lopez-Rubio J. J. Pfrender M. Emrich S. Mohandas N. Dondorp A. M. Wiest O. Haldar K. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature: 2015; 520 683
248. Duke M. V. Paul R. N. Elsohly H. N. Sturtz G. Duke S. O. Localization of artemisinin and artemisitene in foliar tissues of glanded and glandless biotypes of Artemisia annua L. Int J Plant Sci: 1994; 155 365 372
249. Akhila A. Thakur R. S. Popli S. P. Biosynthesis of artemisinin in Artemisia annua. Phytochemistry: 1987; 26 1927 1930
250. Nair M. SR. Basile D. V. Bioconversion of arteannuin B to artemisinin. J Nat Prod: 1993; 56 1559 1566
251. Sangwan R. S. Agarwal K. Luthra R. Thakur R. S. Singh-Sangwan N. Biotransformation of arteannuic acid into arteannuin-B and artemisinin in Artemisia annua. Phytochemistry: 1993; 34 1301 1302
252. Ma D. M. Wang Z. Wang L. Alejos-Gonzales F. Sun M. A. Xie D. Y. A genome-wide scenario of terpene pathways in self-pollinated Artemisia annua. Mol Plant: 2015; 8 1580 1598
253. Bouwmeester H. J. Wallaart T. E. Janssen M. HA. van Loo B. Jansen B. JM. Posthumus M. A. Schmidt C. O. De Kraker J. W. König W. A. Franssen M. CR. Amorpha-4, 11-diene synthase catalyses the first probable step in artemisinin biosynthesis. Phytochemistry: 1999; 52 843 854
254. Ro D. K. Paradise E. M. Ouellet M. Fisher K. J. Newman K. L. Ndungu J. M. Ho K. A. Eachus R. A. Ham T. S. Kirby J. Chang M. CY. Withers S. T. Shiba Y. Sarpong R. Keasling J. D. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature: 2006; 440 940
255. Teoh K. H. Polichuk D. R. Reed D. W. Nowak G. Covello P. S. Artemisia annua L. (Asteraceae) trichome-specific cDNAs reveal CYP71AV1, a cytochrome P450 with a key role in the biosynthesis of the antimalarial sesquiterpene lactone artemisinin. FEBS Lett: 2006; 580 1411 1416
256. Teoh K. H. Polichuk D. R. Reed D. W. Covello P. S. Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annua. Botany: 2009; 87 635 642
257. Zhang Y. Teoh K. H. Reed D. W. Maes L. Goossens A. Olson D. JH. Ross A. RS. Covello P. S. The molecular cloning of artemisinic aldehyde Δ11(13) reductase and its role in glandular trichome-dependent biosynthesis of artemisinin in Artemisia annua. J Biol Chem: 2008; 283 21501 21508
258. Simonnet X. Quennoz M. Carlen C. New Artemisia annua hybrids with high artemisinin content. Acta Horticulturae: 2008; 769 371 373
259. Nicolas D. Xavier S. Myriam G. The genetics of artemisinin content in Artemisia annua L. and the breeding of high yielding cultivars. Curr Med Chem: 2001; 8 1795 1801
260. Cockram J. Hill C. Burns C. Arroo R. RJ. Woolley J. G. Flockart I. Robinson T. Atkinson C. J. Davies M. J. Dungey N. Greenland A. J. Smith L. LMJ. Bentley S. Screening a diverse collection of Artemisia annua germplasm accessions for the antimalarial compound, artemisinin. Plant Genet Resour: 2012; 10 152 154
261. Chen M. Yan T. Shen Q. Lu X. Pan Q. Huang Y. Tang Y. Fu X. Liu M. Jiang W. Lv Z. Shi P. Ma Y. N. Hao X. Zhang L. Li L. Tang K. Glandular trichome-specific WRKY 1 promotes artemisinin biosynthesis in Artemisia annua. New Phytol: 2017; 214 304 316
262. Tang K. Shen Q. Yan T. Fu X. Transgenic approach to increase artemisinin content in Artemisia annua L. Plant Cell Rep: 2014; 33 605 615
263. Ikram N. KBK. Simonsen H. T. A review of biotechnological artemisinin production in plants. Front Plant Sci: 2017; 8 1966
264. Zhang L. Jing F. Li F. Li M. Wang Y. Wang G. Sun X. Tang K. Development of transgenic Artemisia annua (Chinese wormwood) plants with an enhanced content of artemisinin, an effective anti-malarial drug, by hairpin-RNA-mediated gene silencing. Biotechnol Appl Biochem: 2009; 52 199 207
265. Banyai W. Kirdmanee C. Mii M. Supaibulwatana K. Overexpression of farnesyl pyrophosphate synthase (FPS) gene affected artemisinin content and growth of Artemisia annua L. Plant Cell Tissue Organ Cult: 2010; 103 255 265
266. Ma C. Wang H. Lu X. Wang H. Xu G. Liu B. Terpenoid metabolic profiling analysis of transgenic Artemisia annua L. by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. Metabolomics: 2009; 5 497 506
267. Chen Y. Shen Q. Wang Y. Wang T. Wu S. Zhang L. Lu X. Zhang F. Jiang W. Qiu B. Gao E. Sun X. Tang K. The stacked over-expression of FPS, CYP71AV1 and CPR genes leads to the increase of artemisinin level in Artemisia annua L. Plant Biotechnol Rep: 2013; 7 287 295
268. Lu X. Shen Q. Zhang L. Zhang F. Jiang W. Lv Z. Yan T. Fu X. Wang G. Tang K. Promotion of artemisinin biosynthesis in transgenic Artemisia annua by overexpressing ADS, CYP71AV1 and CPR genes. Ind Crops Prod: 2013; 49 380 385
269. Shen Q. Yan T. Fu X. Tang K. Transcriptional regulation of artemisinin biosynthesis in Artemisia annua L. Sci Bull: 2016; 61 18 25
270. Yu Z. X. Li J. X. Yang C. Q. Hu W. L. Wang L. J. Chen X. Y. The jasmonate-responsive AP2/ERF transcription factors AaERF1 and AaERF2 positively regulate artemisinin biosynthesis in Artemisia annua L. Mol Plant: 2012; 5 353 365
271. Lv Z. Wang S. Zhang F. Chen L. Hao X. Pan Q. Fu X. Li L. Sun X. Tang K. Overexpression of a novel NAC domain-containing transcription factor gene (AaNAC1) enhances the content of artemisinin and increases tolerance to drought and Botrytis cinerea in Artemisia annua. Plant Cell Physiol: 2016; 57 1961 1971
272. Martin V. JJ. Pitera D. J. Withers S. T. Newman J. D. Keasling J. D. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol: 2003; 21 796
273. Anthony J. R. Anthony L. C. Nowroozi F. Kwon G. Newman J. D. Keasling J. D. Optimization of the mevalonate-based isoprenoid biosynthetic pathway in Escherichia coli for production of the anti-malarial drug precursor amorpha-4, 11-diene. Metab Eng: 2009; 11 13 19
274. Fuentes P. Zhou F. Erban A. Karcher D. Kopka J. Bock R. A new synthetic biology approach allows transfer of an entire metabolic pathway from a medicinal plant to a biomass crop. Elife: 2016; 5 e13664
275. Paddon C. J. Westfall P. J. Pitera D. J. Benjamin K. Fisher K. McPhee D. Leavell M. D. Tai A. Main A. Eng D. Polichuk D. R. Teoh K. H. Reed D. W. Treynor T. Lenihan J. Jiang H. Fleck M. Bajad S. Dang G. Dengrove D. Diola D. Dorin G. Ellens K. W. Fickes S. Galazzo J. Gaucher S. P. Geistlinger T. Henry R. Hepp M. Horning T. Iqbal T. Kizer L. Lieu B. Melis D. Moss N. Regentin R. Secrest S. Tsuruta H. Vazquez R. Westblade L. F. Xu L. Yu M. Zhang Y. Zhao L. Lievense J. Covello P. S. Keasling J. D. Reiling K. K. Renninger N. S. Newman J. D. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature: 2013; 496 528
276. Peplow M. Synthetic biology's first malaria drug meets market resistance. Nature: 2016; 530 389 390
277. Wani M. C. Taylor H. L. Wall M. E. Coggon P. McPhail A. T. Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc: 1971; 93 2325 2327
278. Wani M. C. Horwitz S. B. Nature as a remarkable chemist: a personal story of the discovery and development of taxol. Anticancer Drugs: 2014; 25 482
279. Ogden L. Taxus (yews) - a highly toxic plant. Vet Hum Toxico: 1988; 30 563 564
280. ® biosynthesis and production: from forests to fermenters. In: Schwab W. Lange B. Wust M. eds. Biotechnology of Natural Products. Cham Springer: 2018; 145 185
281. Weaver B. A. How taxol/paclitaxel kills cancer cells. Mol Biol Cell: 2014; 25 2677 2681
282. Onrubia M. Cusido R. Ramirez K. Hernandez-Vazquez L. Moyano E. Bonfill M. Palazon J. Bioprocessing of plant in vitro systems for the mass production of pharmaceutically important metabolites: paclitaxel and its derivatives. Curr Med Chem: 2013; 20 880 891
283. Gersmann H. Aldred J. Medicinal tree used in chemotherapy drug faces extinction. Available at: https://www.theguardian.com/environment/2011/nov/10/iucn-red-list-tree-chemotherapy Accessed May 23, 2018
284. Onrubia M. Pollier J. Vanden Bossche R. Goethals M. Gevaert K. Moyano E. Vidal-Limon H. Cusidó R. M. Palazón J. Goossens A. Taximin, a conserved plant-specific peptide is involved in the modulation of plant-specialized metabolism. Plant Biotechnol J: 2014; 12 971 983
285. Ramírez-Estrada K. Altabella T. Onrubia M. Moyano E. Notredame C. Osuna L. Vanden Bossche R. Goossens A. Cusido R. M. Palazon J. Transcript profiling of jasmonate-elicited Taxus cells reveals a β -phenylalanine-CoA ligase. Plant Biotechnol J: 2016; 14 85 96
286. The IUCN Red List of Threatened Species, Taxus brevifolia. Available at: https://doi.org/10.2305/IUCN.UK.2013-1.RLTS.T34041A2841142.en Accessed May 23, 2018
287. Nicolaou K. C. Yang Z. Liu J. J. Ueno H. Nantermet P. G. Guy R. K. Claiborne C. F. Renaud J. Couladouros E. A. Paulvannan K. Sorensen E. J. Total synthesis of taxol. Nature: 1994; 367 630
288. Yukimune Y. Tabata H. Higashi Y. Hara Y. Methyl jasmonate-induced overproduction of paclitaxel and baccatin III in Taxus cell suspension cultures. Nat Biotechnol: 1996; 14 1129 1132
289. Ajikumar P. K. Xiao W. H. Tyo K. EJ. Wang Y. Simeon F. Leonard E. Mucha O. Phon T. H. Pfeifer B. Stephanopoulos G. Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Science: 2010; 330 70 74
290. Rai A. Saito K. Yamazaki M. Integrated omics analysis of specialized metabolism in medicinal plants. Plant J: 2017; 90 764 787
291. Medicinal Plant Genomics Resource. Available at: http://medicinalplantgenomics.msu.edu/ Accessed May 23, 2018
292. Zhao D. Y. Hamilton J. P. Pham G. M. Crisovan E. Wiegert-Rininger K. Vaillancourt B. DellaPenna D. Buell C. R. De novo genome assembly of Camptotheca acuminata, a natural source of the anti-cancer compound camptothecin. Gigascience: 2017; 6 1 7
293. Hoopes G. M. Hamilton J. P. Kim J. Zhao D. Wiegert-Rininger K. Crisovan E. Buell C. R. Genome assembly and annotation of the medicinal plant Calotropis gigantea, a producer of anti-cancer and anti-malarial cardenolides. G3 (Bethesda): 2018; 8 385 391
294. Orcae. Online Resource for Community Annotation of Eukaryotes. Available at: http://bioinformatics.psb.ugent.be/orcae/ Accessed May 23, 2018
295. Sterck L. Billiau K. Abeel T. Rouze P. van de Peer Y. ORCAE: online resource for community annotation of eukaryotes. Nat Methods: 2012; 9 1041
296. Transcriptome Characterization, Sequencing, and Assembly of Medicinal Plants Relevant to Human Health. Available at: https://apps.pharmacy.uic.edu/depts/pcrps/MedTranscriptomePlants/ Accessed May 23, 2018
297. Lau W. Sattely E. S. Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone. Science: 2015; 349 1224 1228
298. Li F. S. Weng J. K. Demystifying traditional herbal medicine with modern approaches. Nat Plants: 2017; 3 17109
299. Huang W. Manglik A. Venkatakrishnan A. J. Laeremans T. Feinberg E. N. Sanborn A. L. Kato H. E. Livingston K. E. Thorsen T. S. Kling R. C. Granier S. Gmeiner P. Husbands S. M. Traynor J. R. Weis W. I. Steyaert J. Dror R. O. Kobilka B. K. Structural insights into μ -opioid receptor activation. Nature: 2015; 524 315
300. Gigant B. Wang C. G. Ravelli R. BG. Roussi F. Steinmetz M. O. Curmi P. A. Sobel A. Knossow M. Structural basis for the regulation of tubulin by vinblastine. Nature: 2005; 435 519 522
301. Gaquerel E. Kuhl C. Neumann S. Computational annotation of plant metabolomics profiles via a novel network-assisted approach. Metabolomics: 2013; 9 904 918
302. Naake T. Gaquerel E. MetCirc: navigating mass spectral similarity in high-resolution MS/MS metabolomics data. Bioinformatics: 2017; 33 2419 2420
303. Morreel K. Saeys Y. Dima O. Lu F. C. Van de Peer Y. Vanholme R. Ralph J. Vanholme B. Boerjan W. Systematic structural characterization of metabolites in arabidopsis via candidate substrate-product pair networks. Plant Cell: 2014; 26 929 945
304. Li D. P. Baldwin I. T. Gaquerel E. Navigating natural variation in herbivory-induced secondary metabolism in coyote tobacco populations using MS/MS structural analysis. Proc Natl Acad Sci U S A: 2015; 112 E4147 E4155