Skip to main content

Advertisement

Log in

The biosynthesis and genetic engineering of bioactive indole alkaloids in plants

  • Review Article
  • Published:
Journal of Plant Biology Aims and scope Submit manuscript

Abstract

Indole alkaloids are widely distributed secondary metabolites that exhibit a broad range of pharmacological activities. They are synthesized through plant biosynthetic pathways involving complex enzyme activities and regulatory strategies. Since many compounds of indole alkaloids are structurally too complex to be manufactured economically by chemical synthesis, they have to be isolated from naturally grown or cultivated plants. Therefore, the biotechnological production of high-value plant secondary metabolites in cultivated cells or transgenic plants is potentially an attractive alternative. The present review describes the regulation of indole alkaloids biosynthesis, as well as their pharmacological functions in plants such as anti-microbes, anti-inflammatory and anti-tumor. Furthermore, it discusses different strategies by which the genetic engineering of indole alkaloids biosynthesis through the reconstruction of the pathway achieves high production of specific compounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Almeida CL, Da SAK, Curcino VI, Mathias L, Braz-Filho R, Silva SS, Vieira-da-Motta O (2010) Rauvolfia grandiflora (apocynaceae) extract interferes with staphylococcal density, enterotoxin production and antimicrobial activity. Braz J Microbiol 41:612–620

    Article  Google Scholar 

  • Barleben L, Panjikar S, Ruppert M, Koepke J, Stockigt J (2007) Molecular Architecture of Strictosidine Glucosidase: The Gateway to the Biosynthesis of the Monoterpenoid Indole Alkaloid Family. Plant Cell 19:2886–2897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beets CA, Huang JC, Madala NE, Dubery I (2012) Activation of camalexin biosynthesis in Arabidopsis thaliana in response to perception of bacterial lipopolysaccharides: a gene-to-metabolite study. Planta 236:261–272

    Article  CAS  PubMed  Google Scholar 

  • Berthelot K, Estevez Y, Deffieux A, Peruch F (2012) Isopentenyl diphosphate isomerase: A checkpoint to isoprenoid biosynthesis. Biochimie 94:1621–1634

    Article  CAS  PubMed  Google Scholar 

  • Bottcher C, Westphal L, Schmotz C, Prade E, Scheel D, Glawischnig E (2009) The multifunctional enzyme CYP71B15 (PHYTOALEXIN DEFICIENT3) converts cysteine-indole-3-acetonitrile to camalexin in the indole-3-acetonitrile metabolic network of Arabidopsis thaliana. Plant Cell 21:1830–1845

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Broun P (2004) Transcription factors as tools for metabolic engineering in plants. Curr Opin Plant Biol 7:202–209

    Article  CAS  PubMed  Google Scholar 

  • Burlat V, Oudin A, Courtois M, Rideau M, St-Pierre B (2004) Coexpression of three MEP pathway genes andgeraniol 10-hydroxylase in internal phloem parenchyma of Catharanthus roseus implicates multicellular translocation of intermediates during the biosynthesis of monoterpene indole alkaloids and isoprenoid-derived primary metabolites. Plant J 38:131–141

    Article  CAS  PubMed  Google Scholar 

  • Cai J, Lei LS, Chi DB (2009) Antineoplastic effect of koumine in mice bearing H22 solid tumor. J South Med Univ 29:1851–1852

    CAS  Google Scholar 

  • Cao R, Peng W, Wang Z, Xu A (2007) beta-Carboline alkaloids: biochemical and pharmacological functions. Curr Med Chem 14:479–500

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Dong X, Li Q, Zhou X, Gao S, Chen R, Sun L, Zhang L, Chen W (2013) Biosynthesis of the active compounds of Isatis indigotica based on transcriptome sequencing and metabolites profiling. BMC Genomics 14:857

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chi DB, Li L, Sun LS, Ma WF (2007) Koumine-induced apoptosis of human colonic adenocarcinoma cells: the cell biological mechanism. J South Med Univ 27:994–997

    CAS  Google Scholar 

  • Chu C, Xu J, Cheng D, Li X, Tong S, Yan J, Li Q (2014) Antiproliferative and apoptosis-inducing effects of camptothecin-20(s)-O-(2-pyrazolyl-1)acetic ester in human breast tumor MCF-7 cells. Molecules 19:4941–4955

    Article  PubMed  CAS  Google Scholar 

  • Closa M, Vranova E, Bortolotti C, Bigler L, Arro M, Ferrer A, Gruissem W (2010) The Arabidopsis thaliana FPP synthase isozymes have overlapping and specific functions in isoprenoid biosynthesis, and complete loss of FPP synthase activity causes early developmental arrest. Plant J 63:512–525

    Article  CAS  PubMed  Google Scholar 

  • Courdavault V, Thiersault M, Courtois M, Gantet P, Oudin A, Doireau P, St-Pierre B, Giglioli-Guivarc’H N (2005) CaaXprenyltransferases are essential for expression of genes involvedin the early stages of monoterpenoid biosynthetic pathway in Catharanthus roseus cells. Plant Mol Biol 57:855–870

    Article  CAS  PubMed  Google Scholar 

  • David E. Burke, James M. Cook P. W (1973) Biomimetic synthesis of the bisindole alkaloids villalstonine and alstonisidine. J Am Chem Soc 95:546–552

    Article  Google Scholar 

  • De Luca V, Salim V, Atsumi SM, Yu F (2012) Mining the biodiversity of plants: a revolution in the making. Science 336:1658–1661

    Article  PubMed  CAS  Google Scholar 

  • De Luca V, Salim V, Thamm A, Masada SA, Yu F (2014) Making iridoids/secoiridoids and monoterpenoid indole alkaloids: progress on pathway elucidation. Curr Opin Plant Biol 19:35–42

    Article  PubMed  CAS  Google Scholar 

  • Desgagne-Penix I, Khan MF, Schriemer DC, Cram D, Nowak J, Facchini PJ (2010) Integration of deep transcriptome and proteome analyses reveals the components of alkaloid metabolism in opium poppy cell cultures. BMC Plant Biol 10:252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dudareva N, Klempien A, Muhlemann JK, Kaplan I (2013) Biosynthesis, function and metabolic engineering of plant volatile organic compounds. New Phytol 198:16–32

    Article  CAS  PubMed  Google Scholar 

  • Farrow SC, Hagel JM, Facchini PJ (2012) Transcript and metabolite profiling in cell cultures of 18 plant species that produce benzylisoquinoline alkaloids. Phytochemistry 77:79–88

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Perez F, Almagro L, Pedreno MA, Gomez RL (2013) Synergistic and cytotoxic action of indole alkaloids produced from elicited cell cultures of Catharanthus roseus. Pharm Biol 51:304–310

    Article  CAS  PubMed  Google Scholar 

  • Gantet P, Memelink J (2002) Transcription factors: tools to engineer the production of pharmacologically active plant metabolites. Trends Pharmacol Sci 23:563–569

    Article  CAS  PubMed  Google Scholar 

  • George GM, Ruckle ME, Lloyd JR (2015) Virus-induced gene silencing as a scalable tool to study drought tolerance in plants. Methods Mol Biol 1287:243–253

    Article  CAS  PubMed  Google Scholar 

  • Gerhards N, Neubauer L, Tudzynski P, Li S (2014) Biosynthetic Pathways of Ergot Alkaloids. Toxins 6:3281–3295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giddings LA, Liscombe DK, Hamilton JP, Childs KL, Della Penna D, Buell CR, O’Connor SE (2011) A stereoselective hydroxylation step of alkaloid biosynthesis by a unique cytochrome P450 in Catharanthus roseus. J Biol Chem 286:16751–16757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginis O, Courdavault V, Melin C, Lanoue A, Giglioli-Guivarc’H N, St-Pierre B, Courtois M, Oudin A (2012) Molecular cloning and functional characterization of Catharanthus roseus hydroxymethylbutenyl 4-diphosphate synthase gene promoter from the methyl erythritol phosphate pathway. Mol Biol Rep 39:5433–5447

    Article  CAS  PubMed  Google Scholar 

  • Glawischnig E (2006) The role of cytochrome P450 enzymes in the biosynthesis of camalexin. Biochem Soc Trans 34:1206–1208

    Article  CAS  PubMed  Google Scholar 

  • Glawischnig E, Hansen BG, Olsen CE, Halkier BA (2004) Camalexin is synthesized from indole-3-acetaldoxime, a key branching point between primary and secondary metabolism in Arabidopsis. Proc Natl Acad Sci USA 101:8245–8250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldhaber-Pasillas G, Mustafa N, Verpoorte R (2014) Jasmonic Acid Effect on the Fatty Acid and Terpenoid Indole Alkaloid Accumulation in Cell Suspension Cultures of Catharanthus roseus. Molecules 19:10242–10260

    Article  PubMed  CAS  Google Scholar 

  • Gongora-Castillo E, Childs KL, Fedewa G, Hamilton JP, Liscombe DK, Magallanes-Lundback M, Mandadi KK, Nims E, Runguphan W, Vaillancourt B, Varbanova-Herde M, Dellapenna D, McKnight TD, O’Connor S, Buell CR (2012) Development of transcriptomic resources for interrogating the biosynthesis of monoterpene indole alkaloids in medicinal plant species. PloS One 7:e52506

    Article  CAS  Google Scholar 

  • Goodman HM, Somerville CR, Copenhaver GP, Preuss D, Nierman WC, White O, Eisen JA, Salzberg SL, Fraser CM, Venter JC (1999) Sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana. Nature 402:761–768

    Article  PubMed  Google Scholar 

  • Graziella Collu, Nehir Unver, Anja M.G. Peltenburg-Looman, Robert van der Heijdena, Robert Verpoorte, Johan Memelink (2001) Geraniol 10-hydroxylase1, a cytochrome P450 enzyme involved in terpenoid indole alkaloid biosynthesis. FEBS Letters 508:215–220

    Article  Google Scholar 

  • Grynkiewicz G, Gadzikowska M (2008) Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs. Pharmacol Rep 60:439–463

    CAS  PubMed  Google Scholar 

  • Gu XC, Chen JF, Xiao Y, Di P, Xuan HJ, Zhou X, Zhang L, Chen WS (2012) Overexpression of allene oxide cyclase promoted tanshinone/phenolic acid production in Salvia miltiorrhiza. Plant Cell Rep 31:2247–2259

    Article  CAS  PubMed  Google Scholar 

  • Hamada A, Hibino T, Nakamura T, Takabe T (2001) Na+/H+ antiporter from Synechocystis species PCC 6803, homologous to SOS1, contains an aspartic residue and long C-terminal tail important for the carrier activity. Plant Physiol 125:437–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han M, Heppel SC, Su T, Bogs J, Zu Y, An Z, Rausch T (2013) Enzyme inhibitor studies reveal complex control of methyl-Derythritol 4-phosphate (MEP) pathway enzyme expression in Catharanthus roseus. Plos One 8:e62467

    Article  CAS  Google Scholar 

  • Hasunuma T, Takeno S, Hayashi S, Sendai M, Bamba T, Yoshimura S, Tomizawa K, Fukusaki E, Miyake C (2008) Overexpression of 1-Deoxy-D-xylulose-5-phosphate reductoisomerase gene in chloroplast contributes to increment of isoprenoid production. J Biosci Bioeng 105:518–526

    Article  CAS  PubMed  Google Scholar 

  • Herrmann KM. (1995) The Shikimate Pathway: Early Steps in the Biosynthesis of Aromatic Compounds. Plant Cell 7:907–919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiroshi Ashihara, Alan Crozier, Atsushi Komamine (2011) Monoterpenoid Indole Alkaloid: Plant Metabolism and Biotechnology. Wiley 263–269

    Google Scholar 

  • Hughes EH, Hong SB, Gibson SI, Shanks JV, San KY (2004) Metabolic engineering of the indole pathway in Catharanthus roseus hairy roots and increased accumulation of tryptamine and serpentine. Metab Eng 6:268–276

    Article  CAS  PubMed  Google Scholar 

  • Jakubczyk D, Cheng JZ, O’Connor SE (2014) Biosynthesis of the ergot alkaloids. Nat Prod Rep 31:1328–1338

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Jiang X, Law K, Chen Y, Gu J, Zhang W, Xin H, Sha X, Fang X (2011) Enhanced anti-tumor effect of 9-nitrocamptothecin complexed by hydroxypropyl-beta-cyclodextrin and safety evaluation. Int J Pharm 415:252–258

    Article  CAS  PubMed  Google Scholar 

  • Jimenez J, Riveron-Negrete L, Abdullaev F, Espinosa-Aguirre J, Rodriguez-Arnaiz R (2008) Cytotoxicity of the beta-carboline alkaloids harmine and harmaline in human cell assays in vitro. Exp Toxicol Pathol 60:381–389

    Article  CAS  PubMed  Google Scholar 

  • Jin H, Liu D, Zuo K, Gong Y, Miao Z, Chen Y, Ren W, Sun X, Tang K (2007) Molecular cloning and characterization of Crmdr1, a novel MDR-type ABC transporter gene from Catharanthus roseus. DNA Seq 18:316–325

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Park A, Glatt SJ, Eckert TL, Vanable PA, Scott-Sheldon LA, Carey KB, Ewart CK, Carey MP (2015) Interaction effects between the 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype and family conflict on adolescent alcohol use and misuse. Addiction 110:289–299

    Article  PubMed  Google Scholar 

  • Kim JK, Park GM (2012) Indirubin-3-monoxime exhibits antiinflammatory properties by down-regulating NF-kappaB and JNK signaling pathways in lipopolysaccharide-treated RAW264.7 cells. Inflamm Res 61:319–325

    Article  CAS  PubMed  Google Scholar 

  • Kim MH, Choi YY, Yang G, Cho IH, Nam D, Yang WM (2013) Indirubin, a purple 3,2-bisindole, inhibited allergic contact dermatitis via regulating T helper (Th)-mediated immune system in DNCB-induced model. J Ethnopharmacol 145:214–219

    Article  CAS  PubMed  Google Scholar 

  • Kingston DG (2009) Tubulin-interactive natural products as anticancer agents. J Nat Prod 72:507–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klahre U, Gurba A, Hermann K, Saxenhofer M, Bossolini E, Guerin P M, Kuhlemeier C (2011) Pollinator choice in Petunia depends on two major genetic Loci for floral scent production. Curr Biol 21:730–739

    Article  CAS  PubMed  Google Scholar 

  • Klee HJ (2010) Improving the flavor of fresh fruits: genomics, biochemistry, and biotechnology. New Phytol 187:44–56

    Article  CAS  PubMed  Google Scholar 

  • Klein M, Martinoia E, Hoffmann-Thoma G, Weissenbock G (2000) A membrane-potential dependent ABC-like transporter mediates the vacuolar uptake of rye flavone glucuronides: regulation of glucuronide uptake by glutathione and its conjugates. Plant J 21:289–304

    Article  CAS  PubMed  Google Scholar 

  • Koji Kasai, Takuya Kanno, Mitsuru Akita, Yasuko Ikejiri-Kanno, Kyo Wakasa, Yuzuru Tozawa (2005) Identification of three shikimate kinase genes in rice characterization of their differential expression during panicle development and of the enzymatic activities of the encoded proteins. Planta 222:438–447

    Article  CAS  Google Scholar 

  • Lansiaux A, Bailly C, Houssier C, Colson P, De Pauw-Gillet MC, Frederich M, Tits M, Angenot L (2002) Apoptosis of HL-60 leukemia cells induced by the bisindole alkaloids sungucine and isosungucine from Strychnos icaja. Planta Med 68:591–595

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Lee JE, Kim Y, Lee H, Jun HJ, Lee SJ (2014) Multidrug and toxic compound extrusion protein-1 (MATE1/SLC47A1) is a novel flavonoid transporter. J Agric Food Chem 62:9690–9698

    Article  CAS  PubMed  Google Scholar 

  • Kang Il Lee, Min Ju Kim, Hyongjong Koh, Jin I. Lee, Sim Namkoong, Won Keun Oh, Junsoo Parka (2015) The antihypertensive drug reserpine induces neuronal cell death through inhibition of autophagic flux. Biochem Biophys Res Commun 4:402–408

    Google Scholar 

  • Li C, Zhang ZC, Ghebremariam KM, Wang LH, Wu L, Liang Y (2014) A novel method for the evaluation of virus-induced gene silencing efficiency. Genet Mol Res 13:9443–9452

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Huang Y, Dong F, Li W, Ding L, Yu G, Xu D, Yang Y, Xu X, Tong D (2012) Swainsonine promotes apoptosis in human oesophageal squamous cell carcinoma cells in vitro and in vivo through activation of mitochondrial pathway. J Biosci 37:1005–1016

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Xu X, Huang Y, Ding L, Wang Z, Yu G, Xu D, Li W, Tong D (2012) Swainsonine activates mitochondria-mediated apoptotic pathway in human lung cancer A549 cells and retards the growth of lung cancer xenografts. Int J Biol Sci 8:394–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang Yonghong, Hou Huaxin, Li Danrong, Qin Jing, Qiu Li, Wu Huahui (2000) Studies on in v itro Anticancer Activity of Tryptanthrin B. Chin Trad and Herb Drugs 7:53–55

    Google Scholar 

  • Liao XM, Leung KN (2013) Indirubin-3’-oxime induces mitochondrial dysfunction and triggers growth inhibition and cell cycle arrest in human neuroblastoma cells. Oncol Rep 29:371–379

    CAS  PubMed  Google Scholar 

  • Liscombe DK, OConnor SE (2011) A virus-induced gene silencing approach to understanding alkaloid metabolism in Catharanthus roseus. Phytochemistry 72:1969–1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liscombe DK, Ziegler J, Schmidt J, Ammer C, Facchini PJ (2009) Targeted metabolite and transcript profiling for elucidating enzyme function: isolation of novel N-methyltransferases from three benzylisoquinoline alkaloid-producing species. Plant J 60:729–743

    Article  CAS  PubMed  Google Scholar 

  • Liu W, Chen R, Chen M, Zhang H, Peng M, Yang C, Ming X, Lan X, Liao Z (2012) Tryptophan decarboxylase plays an important role in ajmalicine biosynthesis in Rauvolfia verticillata. Planta 236:239–250

    Article  CAS  PubMed  Google Scholar 

  • Mach J (2012) No more free lunch: using RNA interference in the host to reduce growth of a parasitic plant. Plant Cell 24:2709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCaskill DG, Martin DL, Scott AI (1988) Characterization of Alkaloid Uptake by Catharanthus roseus (L.) G. Don Protoplasts. Plant Physiol 87:402–408

    Article  CAS  PubMed  Google Scholar 

  • Mehrotra S, Goel MK, Srivastava V, Rahman LU (2015) Hairy root biotechnology of Rauwolfia serpentina: a potent approach for the production of pharmaceutically important terpenoid indole alkaloids. Biotechnol Lett 37:253–263

    Article  CAS  PubMed  Google Scholar 

  • Memelink J, Verpoorte R, Kijne JW (2001) ORCA nization of jasmonate-responsive gene expression in alkaloid metabolism. Trends Plant Sci 6:212–219

    Article  CAS  PubMed  Google Scholar 

  • Mentzen WI, Peng J, Ransom N, Nikolau BJ, Wurtele ES (2008) Articulation of three core metabolic processes in Arabidopsis: fatty acid biosynthesis, leucine catabolism and starch metabolism. BMC Plant Biol 8:76

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Miettinen K, Dong L, Navrot N, Schneider T, Burlat V, Pollier J, Woittiez L, van der Krol S, Lugan R, Ilc T, Verpoorte R, Oksman-Caldentey K, Martinoia E, Bouwmeester H, Goossens A, Memelink J, Werck-Reichhart D (2014) The seco-iridoid pathway from Catharanthus roseus. Nat Commun 5:3606

    PubMed  PubMed Central  Google Scholar 

  • Minelli R, Cavalli R, Ellis L, Pettazzoni P, Trotta F, Ciamporcero E, Barrera G, Fantozzi R, Dianzani C, Pili R (2012) Nanospongeencapsulated camptothecin exerts anti-tumor activity in human prostate cancer cells. Eur J Pharm Sci 47:686–694

    Article  CAS  PubMed  Google Scholar 

  • Mithofer A, Boland W (2012) Plant defense against herbivores: chemical aspects. Annu Rev Plant Biol 63:431–450

    Article  PubMed  CAS  Google Scholar 

  • Mok CK, Kang SS, Chan RW, Yue PY, Mak NK, Poon LL, Wong RN, Peiris JS, Chan MC (2014) Anti-inflammatory and antiviral effects of indirubin derivatives in influenza A (H5N1) virus infected primary human peripheral blood-derived macrophages and alveolar epithelial cells. Antiviral Res 106:95–104

    Article  CAS  PubMed  Google Scholar 

  • Moldrup ME, Geu-Flores F, Halkier BA (2013) Assigning gene function in biosynthetic pathways: camalexin and beyond. Plant Cell 25:360–367

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Moldrup ME, Salomonsen B, Geu-Flores F, Olsen CE, Halkier BA (2013) De novo genetic engineering of the camalexin biosynthetic pathway. J Biotechnol 167:296–301

    Article  PubMed  CAS  Google Scholar 

  • Munkert J, Pollier J, Miettinen K, Van Moerkercke A, Payne R, Muller-Uri F, Burlat V, O’Connor SE, Memelink J, Kreis W, Goossens A (2015) Iridoid Synthase Activity Is Common among the Plant Progesterone 5beta-Reductase Family. Mol Plant 8:136–152

    Article  CAS  PubMed  Google Scholar 

  • Murata J, Roepke J, Gordon H, De Luca V (2008) The leaf epidermome of Catharanthus roseus reveals its biochemical specialization. Plant Cell 20:524–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oh KB, Mar W, Kim S, Kim JY, Lee TH, Kim JG, Shin D, Sim CJ, Shin J (2006) Antimicrobial activity and cytotoxicity of bis(indole) alkaloids from the sponge Spongosorites sp. Biol Pharm Bull 29:570–573

    Article  CAS  PubMed  Google Scholar 

  • Oksman-Caldentey KM, Inze D (2004) Plant cell factories in the post-genomic era: new ways to produce designer secondary metabolites. Trends Plant Sci 9:433–440

    Article  CAS  PubMed  Google Scholar 

  • Otani M, Shitan N, Sakai K, Martinoia E, Sato F, Yazaki K (2005) Characterization of vacuolar transport of the endogenous alkaloid berberine in Coptis japonica. Plant Physiol 138:1939–1946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan Q, Wang Q, Yuan F, Xing S, Zhao J, Choi YH, Verpoorte R, Tian Y, Wang G, Tang K (2012) Overexpression of ORCA3 and G10H in Catharanthus roseus plants regulated alkaloid biosynthesis and metabolism revealed by NMR-metabolomics. PloS One 7:e43038

    Article  CAS  Google Scholar 

  • Pan X, Hartley JM, Hartley JA, White KN, Wang Z, Bligh SW (2012) Evodiamine, a dual catalytic inhibitor of type I and II topoisomerases, exhibits enhanced inhibition against camptothecin resistant cells. Phytomedicne 19:618–624

    Article  CAS  Google Scholar 

  • Pedras MS, Minic Z, Abdoli A (2014) The phytoalexin camalexin induces fundamental changes in the proteome of Alternaria brassicicola different from those caused by brassinin. Fungal Biol 118:83–93

    Article  CAS  PubMed  Google Scholar 

  • Peebles CA, Hughes EH, Shanks JV, San KY (2009) Transcriptional response of the terpenoid indole alkaloid pathway to the overexpression of ORCA3 along with jasmonic acid elicitation of Catharanthus roseus hairy roots over time. Metab Eng 11:76–86

    Article  CAS  PubMed  Google Scholar 

  • Suhadolnik RJ, Henderson LM, Hanson JB (1958) Biosynthesis of Ergot Alkaloids. J. Am. Chem. Soc 80:3153–3154

    Article  CAS  Google Scholar 

  • Radwanski ER, Barczak AJ, Last RL (1996) Characterization of tryptophan synthase alpha subunit mutants of Arabidopsis thaliana. Mol Gen Genet 253:353–361

    CAS  PubMed  Google Scholar 

  • Rauhut T, Luberacki B, Seitz HU, Glawischnig E (2009) Inducible expression of a Nep1-like protein serves as a model trigger system of camalexin biosynthesis. Phytochemistry 70:185–189

    Article  CAS  PubMed  Google Scholar 

  • Salim V, Yu F, Altarejos J, De Luca V (2013) Virus-induced gene silencing identifies Catharanthus roseus 7-deoxyloganic acid-7-hydroxylase, a step in iridoid and monoterpene indole alkaloid biosynthesis. Plant J 76:754–765

    Article  CAS  PubMed  Google Scholar 

  • Salvini M, Boccardi TM, Sani E, Bernardi R, Tozzi S, Pugliesi C, Durante M (2008) Alpha-tryptophan synthase of Isatis tinctoria: gene cloning and expression. Plant Physiol Biochem 46:715–723

    Article  CAS  PubMed  Google Scholar 

  • Santos FM, Latorre AO, Hueza IM, Sanches DS, Lippi LL, Gardner DR, Spinosa HS (2011) Increased antitumor efficacy by the combined administration of swainsonine and cisplatin in vivo. Phytomedicne 18:1096–1101

    Article  CAS  Google Scholar 

  • Schiff PL (2006) Ergot and its alkaloids. Am J Pharm Educ 70:98

    Article  PubMed  PubMed Central  Google Scholar 

  • Schluttenhofer C, Pattanaik S, Patra B, Yuan L (2014) Analyses of Catharanthus roseus and Arabidopsis thaliana WRKY transcription factors reveal involvement in jasmonate signaling. BMC Genomics 15:502

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schuhegger R, Rauhut T, Glawischnig E (2007) Regulatory variability of camalexin biosynthesis. J Plant Physiol 164:636–644

    Article  CAS  PubMed  Google Scholar 

  • Shi J, Tan H, Yu XH, Liu Y, Liang W, Ranathunge K, Franke RB, Schreiber L, Wang Y, Kai G, Shanklin J, Ma H, Zhang D (2011) Defective Pollen Wall Is Required for Anther and Microspore Development in Rice and Encodes a Fatty Acyl Carrier Protein Reductase. Plant Cell 23:2225–2246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shitan N, Minami S, Morita M, Hayashida M, Ito S, Takanashi K, Omote H, Moriyama Y, Sugiyama A, Goossens A, Moriyasu M, Yazaki K (2014) Involvement of the leaf-specific multidrug and toxic compound extrusion (MATE) transporter Nt-JAT2 in vacuolar sequestration of nicotine in Nicotiana tabacum. PloS One 9:e108789

    Article  CAS  Google Scholar 

  • Shitan N, Sugiyama A, Yazaki K (2013) Functional analysis of jasmonic acid-responsive secondary metabolite transporters. Methods Mol Biol 1011:241–250

    Article  CAS  PubMed  Google Scholar 

  • Shoji T (2014) ATP-binding cassette and multidrug and toxic compound extrusion transporters in plants: a common theme among diverse detoxification mechanisms. Int Rev Cell Mol Biol 309:303–346

    Article  CAS  PubMed  Google Scholar 

  • Sinharoy S, Pislariu CI, Udvardi MK (2015) A high-throughput RNA interference (RNAi)-based approach using hairy roots for the study of plant-rhizobia interactions. Methods Mol Biol 1287:159–178

    Article  CAS  PubMed  Google Scholar 

  • Sinz A (2008) The development of ergot alkaloids as drugs. Pharm Unserer Zeit 37:306–309

    Article  CAS  PubMed  Google Scholar 

  • Smart LE, Martin JL, Limpalaer M, Bruce TJ, Pickett JA (2013) Responses of herbivore and predatory mites to tomato plants exposed to jasmonic acid seed treatment. J Chemecol 39:1297–1300

    CAS  Google Scholar 

  • Su T, Li Y, Yang H, Ren D (2013) Reply: complexity in camalexin biosynthesis. Plant Cell 25:367–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su T, Xu J, Li Y, Lei L, Zhao L, Yang H, Feng J, Liu G, Ren D (2011) Glutathione-indole-3-acetonitrile is required for camalexin biosynthesis in Arabidopsis thaliana. Plant Cell 23:364–380

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sun J, Peebles CA (2015) Engineering overexpression of ORCA3 and strictosidine glucosidase in Catharanthus roseus hairy roots increases alkaloid production. Protoplasma DOI 10.1007/s00709-015-0881-7

    Google Scholar 

  • Sun Y, Luo H, Li Y, Sun C, Song J, Niu Y, Zhu Y, Dong L, Lv A, Tramontano E, Chen S (2011) Pyrosequencing of the Camptotheca acuminata transcriptome reveals putative genes involved in camptothecin biosynthesis and transport. BMC Genomics 12:533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szymanski DB, Lloyd AM, Marks MD (2000) Progress in the molecular genetic analysis of trichome initiation and morphogenesis in Arabidopsis. Trends Plant Sci 5:214–219

    Article  CAS  PubMed  Google Scholar 

  • Tadeusz Aniszewski (2007) Alkaloid Chemistry, Biological Significance, Applications and Ecological Role. In: Alkaloids -Secrets of Life. Elsevier Tayu M, Ishizaki T, Higuchi K, Kawasaki T (2015) DMSO/Tf2Omediated cross-coupling of tryptamine with substituted aniline to access C3a-N1’-linked pyrroloindoline alkaloids. Org Biomol Chem 13:3863–3865

    Google Scholar 

  • Tewksbury JJ, Nabhan GP. (2001) Seed dispersal. Directed deterrence by capsaicin in chilies. Nature 6845:403–404

    Google Scholar 

  • V Salim, VD Luca (2013) Towards Complete Elucidation of Monoterpene Indole Alkaloid Biosynthesis Pathway: Catharanthus roseus as a Pioneer System. Adv in Bota Res 68:1–37

    Article  CAS  Google Scholar 

  • Valletta A, Trainotti L, Santamaria AR, Pasqua G (2010) Cell-specific expression of tryptophan decarboxylase and 10-hydroxygeraniol oxidoreductase, key genes involved in camptothecin biosynthesis in Camptotheca acuminata Decne (Nyssaceae). BMC Plant Biol 10:69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van der Fits L. (2000) ORCA3, a Jasmonate-Responsive Transcriptional Regulator of Plant Primary and Secondary Metabolism. Science 289:295–297

    Article  PubMed  Google Scholar 

  • Veau B, Courtois M, Oudin A, Chenieux JC, Rideau M, Clastre M (2000) Cloning and expression of cDNAs encoding two enzymes of the MEP pathway in Catharanthus roseus. Biochim Biophys Acta 1517:159–163

    Article  CAS  PubMed  Google Scholar 

  • Vetter HP, Mangold U, Schroder G, Marner FJ, Werck-Reichhart D, Schroder J (1992) Molecular Analysis and Heterologous Expression of an Inducible Cytochrome P-450 Protein from Periwinkle (Catharanthus roseus L.). Plant Physiol 100:998–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vom ED, Soares ESM, Kijne JW, Pasquali G, Memelink J (2007) Identification of a bipartite jasmonate-responsive promoter element in the Catharanthus roseus ORCA3 transcription factor gene that interacts specifically with AT-Hook DNA-binding proteins. Plant Physiol 144:1680–1689

    Article  CAS  Google Scholar 

  • Wallwey C, Li SM (2011) Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes. Nat Prod Rep 28:496–510

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Liu Y, Cai Y, Zhang F, Xia G, Xiang F (2010) Cloning and functional analysis of geraniol 10-hydroxylase, a cytochrome P450 from Swertia mussotii Franch. Biosci Biotechnol Biochem 74:1583–1590

    Article  CAS  PubMed  Google Scholar 

  • Weinhold A, Baldwin IT (2011) Trichome-derived O-acyl sugars are a first meal for caterpillars that tags them for predation. Proc Natl Acad Sci USA 108:7855–7859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winzer T, Gazda V, He Z, Kaminski F, Kern M, Larson TR, Li Y, Meade F, Teodor R, Vaistij FE, Walker C, Bowser TA, Graham IA (2012) A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine. Science 336:1704–1708

    Article  CAS  PubMed  Google Scholar 

  • Xiaoquan Qi, Xiaoya Chen, Yulan Wang (2014) Plant Metabolomics: Methods and Applications. Springer

    Google Scholar 

  • Xu W, Gavia DJ, Tang Y (2014) Biosynthesis of fungal indole alkaloids. Nat Prod Rep 31:1474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto Y, Fujita M, Koma H, Yamamori M, Nakamura T, Okamura N, Yagami T (2011) 15-Deoxy-Delta12,14-prostaglandin J2 enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPARgamma pathways. Biochem Biophys Res Commun 410:563–567

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Zuo WJ, Zhao YX, Dong WH, Mei WL, Dai HF (2012) Indole alkaloids from Kopsia hainanensis and evaluation of their antimicrobial activity. Planta Med 78:1881–1884

    Article  CAS  PubMed  Google Scholar 

  • Yazaki K (2005) Transporters of secondary metabolites. Curr Opin Plant Biol 8:301–307

    Article  CAS  PubMed  Google Scholar 

  • You N, Liu W, Wang T, Ji R, Wang X, Gong Z, Dou K, Tao K (2012) Swainsonine inhibits growth and potentiates the cytotoxic effect of paclitaxel in hepatocellular carcinoma in vitro and in vivo. Oncol Rep 28:2091–2100

    CAS  PubMed  Google Scholar 

  • Zhang H, Hedhili S, Montiel G, Zhang Y, Chatel G, Pre M, Gantet P, Memelink J (2011) The basic helix-loop-helix transcription factor CrMYC2 controls the jasmonate-responsive expression of the ORCA genes that regulate alkaloid biosynthesis in Catharanthus roseus. Plant J 67:61–71

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Blaylock LA, Harrison MJ (2010) Two Medicago truncatula half-ABC transporters are essential for arbuscule development in arbuscular mycorrhizal symbiosis. Plant Cell 22:1483–1497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang R, Wang B, Ouyang J, Li J, Wang Y (2008) Arabidopsis indole synthase, a homolog of tryptophan synthase alpha, is an enzyme involved in the Trp-independent indole-containing metabolite biosynthesis. J Integr Plant Biol 50:1070–1077

    Article  CAS  PubMed  Google Scholar 

  • Zhao B, Moochhala SM, Tham SY (2004) Biologically active components of Physostigma venenosum. J Chromatogr B 812:183–192

    Article  CAS  Google Scholar 

  • Ziegler J, Facchini PJ (2008) Alkaloid biosynthesis: metabolism and trafficking. Annu Rev Plant Biol 59:735–769

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Hexin Tan, Lei Zhang or Yong Diao.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, Y., Tan, H., Guo, Z. et al. The biosynthesis and genetic engineering of bioactive indole alkaloids in plants. J. Plant Biol. 59, 203–214 (2016). https://doi.org/10.1007/s12374-016-0032-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12374-016-0032-5

Keywords

Navigation