Abstract
Catharanthus roseus synthesizes one of the most structurally, chemically and biologically active phytomolecules monoterpenoids indole alkaloids (MIAs) with having a wide range of pharmaceutical activities. Being the sole source of antineoplastic MIAs vinblastine and vincristine C. roseus has become one of the most valued plant. The low in planta availability of these MIAs and unavailability of alternative chemical synthesis system has enhanced their demand and equally let to the exorbitant market cost. To bridge this gap alternative production systems have been investigated using MIAs metabolic engineering (ME) in the homologous and heterologous systems. The availability of improved recombinant technologies along with genomics and metabolomics tools has opened the door of tremendous new potentials of ME. To encash these potentials of ME for MIAs pathway, efforts were made by expressing constitutive structure biosynthesis enzymes, transporters, and transcription factors of C. roseus MIAs biosynthesis in both homologous and heterologous systems. Here we review the knowledge of C. roseus MIAs pathway metabolic engineering in homologous and heterologous systems, gained in the past 35 years of C. roseus research.
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References
Ajitkumar PK et al (2010) Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science 330(6000):70–74
Amirkia V, Heinrich M (2014) Alkaloids as drug leads – A predictive structural and biodiversity-based analysis. Phytochem Lett 10:48–53
Asada K, Salim V, Masada-Atsumi S, Edmunds E, Nagatoshi M, Terasaka K, Mizukami H, De Luca V (2013) A 7-deoxyloganetic acid glucosyltransferase contributes a key step in secologanin biosynthesis in Madagascar periwinkle. Plant Cell 25:4123–4134
Ayora-Talavera T, Chappell J, Lozoya-Gloria E et al (2002) Overexpression in Catharanthus roseus hairy roots of a truncated hamster 3-hydroxy-3-methylglutaryl-CoA reductase gene. Appl Biochem Biotech 97:135–145
Bailey JE (1991) Toward a Science of Metabolic Engineering. Science 252:1668–1675
Banyai W, Kirdmanee C, Mii M, Supaibulwatana K (2010) Overexpression of farnesyl pyrophosphate synthase (FPS) gene affected artemisinin content and growth of Artemisia annua L. Plant Cell Tiss Org Cult 103:255–265
Brown S, Clastre M, Courdavault V, O’Connor S (2015) De novo production of the plant-derived alkaloid strictosidine in yeast. Proc Natl Acad Sci USA 112:3205–3210
Buckingham J (2010) Dictionary of alkaloids, 1st edn. CRC Press, Boca Raton, FL
Canel C, Lopes-Cardoso M, Whitmer S et al (1998) Effects of over-expression of strictosidine synthase and tryptophan decarboxylase on alkaloid production by cell cultures of Catharanthus roseus. Planta 205:414–419
Carqueijeiro I, Bernonville TD, Lanoue A, Dang TT et al (2018) A BAHD acyltransferase catalyzing 19-O-acetylation of tabersonine derivatives in roots of Catharanthus roseus enables combinatorial synthesis of monoterpene indole alkaloids. Plant J 94:469–484
Chang K, Qiu F, Chen M, Zeng L, Liu X, Yang C et al (2014) Engineering the MEP pathway enhanced ajmalicine biosynthesis. Biotechnol Appl Biochem 6:249–255
Charlwood BV, Pletsch M (2002) Manipulation of Natural Product Accumulation in Plants Through Genetic Engineering. Journal of Herbs, Spi Med Plants 9:139–151
Chung IM, Hong SB, Peebles CAM et al (2007) Effect of the engineered indole pathway on accumulation of phenolic compounds in Catharanthus roseus hairy roots. Biotech Prog 23:327–332
Collu G, Unver N, Peltenburg-Looman AM et al (2001) Geraniol 10-hydroxylase, a cytochrome P450 enzyme involved in terpenoid indole alkaloid biosynthesis. FEBS Lett 508:215–220
Cordell GA (1981) Introduction to alkaloids, 1st edn. Wiley, New York
Courdavault V, Papon N, Clastre M, Giglioli-Guivarch N, St-Pierre B, Burlat V, (2014) A look inside an alkaloid multisite plant: the Catharanthus logistics. Curr Opin Plant Biol 19:43–50
Dai Z et al (2013) Metabolic engineering of Saccharomyces cerevisiae for production of ginsenosides. Metab Eng 20:146–156
Di Fiore S, Fisher N, Schillberg S (2004) Transient gene expression of recombinant terpenoid indole alkaloid enzymes in Catharanthus roseus leaves. Plant Mol Biol Rep 22:15–22
Fossati E et al (2014) Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae. Nat Commun 5:3283
Geu-Flores F, Sherden NH, Courdavault V, Burlat V, Glenn WS, Wu C, Nims E, Cui Y, O’Connor SE (2012) An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis. Nature 492:138–142
Giddings LA, Liscombe DK, Hamilton JP, Childs KL et al (2011) A stereoselective hydroxylation step of alkaloid biosynthesis by a unique cytochrome P450 in Catharanthus roseus. J. Biol. Chem. 286:16751–16757
Hawkins KM, Smolke CD (2008) Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae. Nat Chem Biol 4(9):564–573
Hong SB, Peebles CA, Shanks JV et al (2006) Expression of the Arabidopsis feedback-insensitive anthranilate synthase holoenzyme and tryptophan decarboxylase genes in Catharanthus roseus hairy roots. J Biotechnol 122:28–38
Horwitz SB (1994) How to make Taxol from scratch. Nature 367:593–594
Hughes EH, Hong SB, Gibson SI et al (2004) Metabolic engineering of the indole pathway in Catharanthus roseus hairy roots and increased accumulation of tryptamine and serpentine. Metab Eng 6:268–276
Jaggi M, Kumar S, Sinha AK (2011) Overexpression of an apoplastic peroxidase gene CrPrx in transgenic hairy root lines of Catharanthus roseus. Appl Microbiol Biotechnol 90:1005–1016
Julsing KM, Quax JW, Oliver K (2007) The engineering of medicinal plants: prospects and limitations of medicinal plant biotechnology. In: Kayser O, Quax WJ (eds) Medicinal Plant Biotechnology. Wiley, Weinheim, pp 3–8
Kellner F, Kim J, Clavijo BJ, Hamilton JP, Childs KL, Vaillancourt B, Cepela J, Habermann M, Steuernagel B, Clissold L, McLay K, Buell CR, Oonnor SE (2015) Genome-guided investigation of plant natural product biosynthesis. Plant J 82:680–692
Kingston DGI (1994) Taxol: the chemistry and structure-activity relationships of a novel anticancer agent. Trends Biotechnol. 12:222–227
Laflamme P, St-Pierre B, De Luca V (2001) Molecular and biochemical analysis of a Madagascar periwinkle root-specific minovincinine-19- hydroxy-O-acetyltransferase. Plant Physiol. 125:189–198
Li CY, Leopold AL, Sander GW et al (2013) The ORCA2 transcription factor plays a key role in regulation of the terpenoid indole alkaloid pathway. BMC Plant Biol 13:155
Liu Y, Patra B, Pattanaik S, Wang Y, Yuan L (2019) GATA and phytochorome interacting factor transcription factors regulates light induced vindoline biosynthesis in Catharanthus roseus. Plant Phy 180:1336–1350
Liu DH, Ren WW, Cui LJ et al (2011) Enhanced accumulation of catharanthine and vindoline in Catharanthus roseus hairy roots by overexpression of transcriptional factor ORCA2. Afr J Biotechnol 10:3260–3268
Magnotta M, Murata J, Chen J et al (2007) Expression of deacetylvindoline-4-O-acetyltransferase in Catharanthus roseus hairy roots. Phytochemistry 68:1922–1931
Mathur AK, Mathur A, Seth R, Verma P, Vyas D (2006) Biotechnological interventions in designing speciality medicinal herbs for twenty first century: Some emerging trends in pathway modulation through metabolic engineering. In: Sharma RK, Arora R (eds) Herbal drugs: a twenty first century perspective. Jaypee Brothers Medical Publishers, New Delhi, pp 83–94
Miettinen K, Dong L, Navrot N, Schneider T, Burlat V, Pollier J et al (2014) The seco-iridoid pathway from Catharanthus roseus. Nat Commun 5:1–12
Minami H et al (2008) Microbial production of plant benzylisoquinoline alkaloids. Proc Natl Acad Sci USA 105(21):7393–7398
Moerkercke AV, Steensma P, Gariboldis I, Espozs J, Purnamas P, Schweizer F, Miettinen K, Bossche RV, De Clercq R, Memelink J, Goossens A (2016) The basic helix-loop-helix transcription factor BIS2 is essential for monoterpenoid indole alkaloids production in the medicinal plant Catharanthus roseus. The Plant J 88:3–12
Mortensen S, Bernal-Franco D, Cole LF, Sathitloetsakun S, Cram EJ, Lee-Parsons CWT (2019) EASI: Transformation: an efficient transient expression method for analysing gene function in Catharanthus roseus seedlings. Front Plant Sci 20:755
Moses T et al (2014) Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16α hydroxylase from Bupleurum falcatum. Proc Natl Acad Sci USA 111(4):1634–1639
Nakagawa A et al (2014) (R, S)-Tetrahydropapaveroline production by stepwise fermentation using engineered Escherichia coli. Sci Rep 4:6695
Nobel RL (1990) The discovery of the vinca alkaloids chemotherapeutic agents against cancer. Biochem Cell Biol. 68:1344–1351
Pan Q, Rianika N, Mustafa Tang K, Choi YH, Verpoorte R (2016) Monoterpenoid indole alkaloids biosynthesis and its regulation in Catharanthus roseus: a literature review from genes to metabolites. Phytochem Rev 15:221–250
Pan Q, Wang Q, Yuan F, Xing S et al (2012) Overexpression of ORCA3 and G10H in Catharanthus roseus plants regulated alkaloid biosynthesis and metabolism revealed by NMR-metabolomics. PLoS ONE 7:1–14
Peebles CAM, EH, Shanks JV et al (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
Peebles CAM, Sander GW, Hughes EH et al (2011) The expression of 1-deoxy-D-xylulose synthase and geraniol-10-hydroxylase or anthranilate synthase increases terpenoid indole alkaloid accumulation in Catharanthus roseus hairy roots. Metab Eng 13:234–240
Qu Y, Easson MLAE, Froese J, Simionescu R, Hudlicky T, De Luca V (2015) Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast. Proc Natl Acad Sci USA 112:6224–6229
Ro D-K et al (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440(7086):940–943
Roberts SC (2007) Production and engineering of terpenoids in plant cell culture. Nature Chem Biol 3:387–395
Saiman MZ, Miettinen K, Mustafa NR, Choi YH, Verpoorte R, Schulte AE (2018) Metabolic alteration of Catharanthus roseus cell suspension cultures overexpressing geraniol synthase in the plastids or cytosol. Plant Cell Tissue Org Cult. 134:41–53
Salim V, Wiens B, Masada-Atsumi S, Yu F, De Luca V (2014) 7-Deoxyloganetic acid synthase catalyzes a key 3 step oxidation to form 7-deoxyloganetic acid in Catharanthus roseus iridoid biosynthesis. Phytochemistry 101:23–31
Santos CN, Koffas M, Stephanopoulos G (2011) Optimization of a heterologous pathway for the production of flavonoids from glucose. Metab Eng 13(4):392–400
Sarma RK, Shilpashree HB, Nagegowda DA (2018) Terpene moiety enhancement by overexpression of geranyl (geranyl) diphosphate synthase and geraniol synthase elevates monomeric and dimeric monoterpene indole alkaloids in transgenic Catharanthus roseus. Front. Plant Sci. 9:942
Schwender J (2008) Metabolic flux analysis as a tool in metabolic engineering of plants. Curr Opin Biotech 19:131–137
Sharma A, Verma N, Verma P, Verma RK, Mathur A, Mathur AK (2017a) Optimization of a Bacopa monnieri-based genetic transformation model for testing the expression efficiency of pathway gene constructs of medicinal crops. Vitro Cell Dev Biol 53:22–32
Sharma A, Verma P, Mathur A, Mathur AK (2017b) Genetic engineering approach using early Vinca alkaloid biosynthesis genes led to increased tryptamine and terpenoid indole alkaloids biosynthesis in differentiating cultures of Catharanthus roseus. Protoplasma 255:425–435
Sharma A, Verma P, Mathur A, Mathur AK (2018) Overexpression of tryptophan decarboxylase and strictosidine synthase enhanced terpenoid indole alkaloids pathway activity and antineoplastic vinblastine biosynthesis in Catharanthus roseus. Protoplasma 255:1281–1294
Sharma A, Mathur AK, Ganapathy J, Joshi B, Patel P (2019) Effect of abiotic elicitation and pathway precursors feegins over terpenoid indole alkaloids production in multiple shoot and callus cultures of C roseus. Biologia 74:543–553
Schweizer F, Colinas M, Pollier J, Van Moerkercke A, Vanden Bossche R, de Clercq R, Goossens A (2018) An engineered combinatorial module of transcription factors boosts production of monoterpenoid indole alkaloids in Catharanthus roseus. Metab Eng 48:150–162
Stavrinides A, Tatsis EC, Foureau E, Caputi L, Kellner F, Courdavault V, Oonnor SE (2015) Unlocking the diversity of alkaloids in Catharanthus roseus: nuclear localization suggests metabolic channeling in secondary metabolism. Chem Biol 22:336–341
Sun J, Peebles CAM (2015) Engineering overexpression of ORCA3 and strictosidine glucosidase in Catharanthus roseus hairy roots increases alkaloid production. Protoplasma. 5:2. https://doi.org/10.1007/s00709-015-0881-7
Sun J, Zhao S, Shanks JV, Peebles CAM (2018) Expression of tabersonine 16-hydroxylase and 16-hydroxytabersonine-O-methyltransferase in Catharanthus roseus hairy roots. Biotechnol Bioeng 115:673–683
Suttipantaa N, Pattanaika S, Kulshrestha M et al (2011) The transcription factor CrWRKY1 positively regulates the terpenoid indole alkaloids biosynthesis in Catharanthus roseus. Plant Physiol 157:2081–2093
Taha HS, Abo-Aba SEM, El-Hamshary OIM et al (2008) In vitro studies on Egyptian Catharanthus roseus (L.) G. Don: III. Effects of extra tryptophan decarboxylase and strictosidine synthase genes copies in indole alkaloid production. Res J Cell Mol Biol 2:18–23
Tang KX, Liu DH, Wang YL, Cui LJ, Ren WW, Sun XF (2011) Overexpression of transcriptional factor ORCA3 increases the accumulation of catharanthine and vindoline in Catharanthus roseus hairy roots. Russ J Plant Physiol 58:415–422
Thamm AMK, Qu Y, De Luca V (2016) Discovery and metabolic engineering of iridoid/secoiridoid and monoterpenoid indole alkaloid biosynthesis. Phytochem Rev 15:339–361
van der Fits L, Memelink J (2000) ORCA3, a jasmonate-responsive transcriptional regulator of plant primary and secondary metabolism. Science 289:295–297
Verma P, Mathur AK (2011) Agrobacterium tumefaciens mediated transgenic plant production via direct shoot bud organogenesis from pre-plasmolyzed leaf explants of Catharanthus roseus. Biotechnol Lett 33:1053–1060
Verma P, Sharma A, Khan SA, Shanker K, Mathur AK (2014) Morphogenetic and chemical stability of long term maintained Agrobacgterium-mediated transgenic Catharnanthus roseus plants. Nat Prod Res 29:315–320
Verma P, Sharma A, Khan SA, Shanker K, Mathur AK (2015) Over-expression of Catharanthus roseus tryptophan decarboxylase and strictosidine synthase in rol gene integrated transgenic cell suspensions of Vinca minor. Protoplasma 252:373–381
Verma P, Mathur AK, Khan SA, Verma N, Sharma A (2017) Transgenic studies for modulating terpenoid indole alkaloids paghway in Catharnanthus roseus present status and future options. Phytochem Rev 16:19–54
Verpoorte R, Alfermann AW (2000) Metabolic engineering of plant secondary metabolism. In: Verpoorte R, Alfermann AW (eds). Kluwer Academic Publishers, Dordrecht.
Wang CT, Liu H, Gao XS et al (2010) Overexpression of G10H and ORCA3 in the hairy roots of Catharanthus roseus improves catharanthine production. Plant Cell Rep 29:887–894
Wang Q, Xing S, Pan Q et al (2012) Development of efficient Catharanthus roseus regeneration and transformation system using agrobacterium tumefaciens and hypocotyls as explants. BMC Biotechnol 12:34
Whitmer S, van der Heijden R, Verpoorte R (2002a) Effect of precursor feeding on alkaloid accumulation by a strictosidine synthase over-expressing transgenic cell line S1 of Catharanthus roseus. Plant Cell Tissue Organ Cult 69:85–93
Whitmer S, van der Heijden R, Verpoorte R (2002b) Effect of precursor feeding on alkaloid accumulation by a tryptophan decarboxylase over-expressing transgenic cell line T22 of Catharanthus roseus. J Biotechnol 96:193–203
Whitmer S, Canel C, van der Heijden R, Verpoorte R (2004) Long term instability of alkaloid production by stably transformed cell lines of Catharanthus roseus. Plant Cell Tiss Org Cult 74:73–80
Wilson SA, Roberts SC (2014) Metabolic engineering approaches for production of biochemicals in food and medicinal plants. Curr Opin Biotech 26:174–182
Yu F, De Luca V (2013) ATP-binding cassette transporter controls leaf surface secretion of anticancer drug components in Catharanthus roseus. Proc Natl Acad Sci USA 110:15830–15835
Zhou ML, Zhu XM, Shao JR, Wu YM, Tang YX (2010) Transcriptional response of the catharanthine biosynthesis pathway to methyl jasmonate/nitric oxide elicitation in Catharanthus roseus hairy root culture. App Microbiol Biotechnol 88:737–750
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AS is highly grateful to the Science and Engineering Research Board, Department of Science and Technology, Government of India (Grant No. SRG/2019/000130) and UTU Research Promotion Scheme (Grant No. UTU/RPS/1431–5/2019).
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Sharma, A., Amin, D., Sankaranarayanan, A. et al. Present status of Catharanthus roseus monoterpenoid indole alkaloids engineering in homo- and hetero-logous systems. Biotechnol Lett 42, 11–23 (2020). https://doi.org/10.1007/s10529-019-02757-4
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DOI: https://doi.org/10.1007/s10529-019-02757-4