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Artemisia annua - Pharmacology and Biotechnology pp 173–204Cite as

Recent Advances to Enhance Yield of Artemisinin: A Novel Antimalarial Compound, in Artemisia annua L. Plants

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Abstract

Malaria is probably as old as mankind and continues to affect millions of people throughout the world. Today, some 500 million people in Africa, India, Southeast Asia, and South America are exposed to endemic malaria, and it is estimated to cause one and half million deaths annually, one million of which are children. As a consequence, effective therapeutic agents against malaria are continuously being sought, especially against those strains of Plasmodium falciparum, which have become resistant to nearly all antimalarial drugs, including chloroquine and quinine. In the absence of reports of artemisinin resistance in malaria parasite, WHO now recommends the use of artemisinin-based combination therapies (ACTs) with formulations containing an artemisinin derivative. Artemisinin, a sesquiterpene endoperoxide lactone, is isolated from the shoots of Artemisia annua L. plants. Apart from a novel and potent antimalarial drug, artemisinin and its derivatives are also used in therapies against hepatitis, leishmaniasis, and schistosomiasis. Artemisinin also possess lethal activities against cancerous cells, fungi, and bacteria. It has also shown to be immune-suppressant in mammals and a potent herbicide. Despite of its immense commercial value, the production of artemisinin is not cost-effective because of its low concentration (0.01–1.1 %) in the plant. Moreover, its de novo synthesis is complex, uneconomical and gives low yields. Further, classical breeding and selection techniques have failed to develop high-yielding strains of A. annua L. plants. Efforts are therefore, needed to elucidate the complex pathway of artemisinin biosynthesis and its biochemical and molecular regulation. Non-conventional approaches have to be developed to evolve novel strains of the plant to optimize and scale up the production of artemisinin in bulk and make it available to ACT manufacturers at a price much lower than their current cost in turn making an important contribution toward attaining the goals of global malaria eradication programs. The details of past and current status of both conventional and non-conventional approaches for enhancing artemisinin content in A. annua L. plants and its yield have been discussed in this chapter.

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References

  • Abdin MZ, Israr M, Rehman RU, Jain SK (2003) Artemisinin, a novel antimalarial drug: biochemical and molecular approaches for enhanced production. Planta Med 69:289–299

    PubMed  CAS  Google Scholar 

  • Acton N, Klayman DL, Rollman IJ (1985) Reductive electrochemical HPLC assay for artemisinin (qinghaosu). Planta Med 5:445--446

    Google Scholar 

  • Acton N, Roth RS (1985) On the conversion of dihydroartemisinic acid into artemisinin. J Org Chem 57:3610–3614

    Google Scholar 

  • Akhila A, Kumkum R, Thakur RS (1990) Biosynthesis of artemisinin in Artemisia annua. Phytochemistry 29:2129–2132

    CAS  Google Scholar 

  • Akiyoshi DE, Klee H, Amasino R, Nester EW, Gordon MP (1984) T-DNA of Agrobacterium tumefaciens encodes an enzyme of cytokinin biosynthesis. Proc Natl Acad Sci USA 81:5994–5998

    PubMed  CAS  Google Scholar 

  • Aquil S, Husaini AM, Abdin MZ, Rather GN (2009) Overexpression of HMG-CoA reductase gene leads to enhanced artemisinin biosynthesis in transgenic A. annua L. plants. Planta Med 75:1–6

    Google Scholar 

  • Attucci S, Aitken SM, Ibrahim RK, Gulick PJA (1995) cDNA encoding farnesyl pyrophosphate synthesis in white lupine. Plant Physiol 108:835–836

    PubMed  CAS  Google Scholar 

  • Avery MA, Chong WKM, Jennings-White C (1992) Stereoselective total synthesis of (+)-artemisinin the antimalarial constituent of Artemisia annua L. J Am Chem Soc 114:974–979

    CAS  Google Scholar 

  • Balachandran S, Vishwakarma RA, Popli SP (1987) Chemical investigation of some Artemisia annua Species: search for artemisinin or other related sesquiterpene lactones with a peroxides bridge. Ind J Pharma Sci 49:152--154

    Google Scholar 

  • Barkovich R, Liao JC (2001) Metabolic engineering of isoprenoids. Metab Eng 3:27--39

    Google Scholar 

  • Bertea CM, Freije JR, van der Woude H, Verstappen FW, Perk L, Marquez V, de Kraker JW, Posthumus MA, Jansen BJ, de Groot A, Franssen MC, Bouwmeester HJ (2005) Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua. Planta Med 71:40–47

    PubMed  CAS  Google Scholar 

  • Borrmann S, Szlezak N, Faucher JF, Matsiegui PB, Neubauer R, Biner RK, Lell B, Kremsner PG (2001) Artesunate and praziquantel for the treatment of Shistosoma haematobium infections: a doubleblind, randomized, placebo-controlled study. J Infect Dis 184:1363–1366

    PubMed  CAS  Google Scholar 

  • Bouwmeester HJ, Wallaart TE, Janssen MH, van Loo B, Jansen BJ, Posthumus MA, Schmidt CO, de Kraker JW, Knig WA, Franssen MC (1999) Amorpha-4,11-diene synthase catalyze the first probable step in artemisinin biosynthesis. Phytochemistry 52:843–854

    PubMed  CAS  Google Scholar 

  • Brown GD (1994) Secondary metabolism in tissue culture of Artemisia annua. J Nat Prod 57(7):975–977

    CAS  Google Scholar 

  • Brown GD, Sy LK (2004) In vivo transformations of dihydroartemisinic acid in Artemisia annua plants. Tetrahedron 60:1139–1159

    Google Scholar 

  • Cai Y, Jia JW, Crock J, Lin ZX, Chen XY, Croteau RA (2002) cDNA clone for bcaryophyllene synthase from Artemisia annua. Phytochem 61:523--529

    Google Scholar 

  • Cane DE (1990) Enzymatic formation of sesquiterpenes. Chem Rev 90:1089–1103

    CAS  Google Scholar 

  • Chang YJ, Song SH, Park SH, Kim SU (2000) Amorpha-4, 11-diene synthase of Artemisia annua: cDNA isolation and bacterial expression of a terpene synthase involved in artemisinin biosynthesis. Arch Biochem Biophys 383:178–184

    PubMed  CAS  Google Scholar 

  • Charels DJ, Cebert E, Simon JE (1991) Characterization of essential oils of Artemisia annua L. J Ess Oil Res 3:33--39

    Google Scholar 

  • Charles DJ, Simon JE, Wood KV, Heinsten P (1990) Germplasm variation in artemisinin content of Artemisinin annua using an alternative method of artemisinin analysis from crude plant extracts. J Nat Prod 53:157–160

    CAS  Google Scholar 

  • Charlwood BV, Pletsch M (2002) Manipulation of natural product accumulation in plants through genetic engineering. J Herbs Spices Med Plants 9:139–151

    CAS  Google Scholar 

  • Chaudhary V, Kapoor R, Bhatnagar AK (2008) Effectiveness of two arbuscular mycorrhizal fungi on concentrations of essential oil and artemisinin in three accessions of Artemisia annua L. Appl Soil Ecol 40:174–181

    Google Scholar 

  • Chen DH, Meng Y, Ye HC, Li GF, Chen XY (1998) Cultures of transgenic Artemisia annua hairy root with cadinene synthase gene. Acta Bot Sin 40:711–714

    CAS  Google Scholar 

  • Chen D, Ye H, Li G (2000) Expression of a chimeric farnesyl diphosphate synthase gene in Artemisia annua L. transgenic plants via Agrobacterium tumefaciens-mediated transformation. Plant Sci 155:179–185

    PubMed  CAS  Google Scholar 

  • Chen D, Liu C, Ye H, Li G, Liu B, Meng Y, Chen X (1999) Ri-mediated transformation of Artemisia annua with a recombinant farnesyl diphosphate synthase gene for artemisinin production. Plant Cell, Tissue Organ Cult 57:157–162

    CAS  Google Scholar 

  • Chen FT, Zang GH (1987) Studies on several physiological factors on artemisinin synthesis in Artemisia annua L. Plant Physiol 5:26--30

    Google Scholar 

  • CIMAP (India) Annual Project Report (1988--1989) Development of Agrotechnologies for Artemisia annua for antimalarial drug, artemisinin

    Google Scholar 

  • CIMAP (India) Annual Project Report (1986--1987) Development of Agrotechnologies for Artemisia annua for antimalarial drug, artemisinin

    Google Scholar 

  • Cyranoski D (2004) Campaign to fight malaria hit by surge in demand for medicine. Nature 432(7015):259

    PubMed  CAS  Google Scholar 

  • de Kraker J, Schurink M, Franssen MCR, König WA, Groot A, Bouwmeester HJ (2003) Hydroxylation of sesquiterpenes by enzymes from chicory (Cychorium intybus L.) roots. Tetrahedron 59:409–418

    Google Scholar 

  • Delabays N, Benakis A, Collet G (1993) Selection and breeding for high artemisinin (qinghaosu) yielding strains of Artemisia annua. Acta Hort 330:203–206

    Google Scholar 

  • Delourme D, Lacroute F, Karst F (1994) Cloning of an Arabidopsis thaliana cDNA coding for farnesyl diphosphate synthase by function complementation in yeast. Plant Mol Biol 26:1867–1873

    PubMed  CAS  Google Scholar 

  • Delabays N, Simonnet X, Gaudin M (2001) The genetics of artemisinin content in Artemisia annua and the breeding of high yielding cultivars. Curr Med Chem 8:1795–1801

    PubMed  CAS  Google Scholar 

  • Duke SO, Paul RN (1993) Development and fine structure of the glandular trichomes of Artemisia annua L. Int J Plant Sci 154:107–118

    Google Scholar 

  • Duke MV, Paul RN (1994) Localization of artemisinin and artemisitene in foliar tissue of glanded and glandless biotypes of Artemisia annua. Int J Plant Sci 155:365–372

    Google Scholar 

  • Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR (2001) The anti-malarial artesunate is also active against cancer. Int J Oncol 18:767–773

    PubMed  CAS  Google Scholar 

  • ElSohly HN (1990) A large-scale extraction technique of artemisinin from Artemisia annua. J Nat Prod 53:1560–1564

    CAS  Google Scholar 

  • Farmer WR, Liao JC (2001) Precursor balancing for metabolic engineering of lycopene production in Escherichia coli. Biotechnol Prog 17:57--61

    Google Scholar 

  • Ferreira JFS, Simon JE, Janick J (1995) Developmental studies of Artemisia annua: flowering and artemisinin production under greenhouse and field conditions. Planta Med 61:167–170

    PubMed  CAS  Google Scholar 

  • Ferreira JFS, Janick J (1996) Distribution of artemisinin in Artemisia annua. In: Janick J (ed) Progress in new crops. ASHS Press, Arlington, VA, pp 579–584

    Google Scholar 

  • Ferreira JFS, Duke SO (1997) Approaches for maximizing biosynthesis of medicinal plant secondary metabolites. AgBiotech News Inf 9:309N–316N

    Google Scholar 

  • Fulzele DP, Heble MR, Rao PS (1995) Production of terpenoid from Artemisia annua L. plantlet cultures in bioreactor. J Biotechnol 40:139–143

    CAS  Google Scholar 

  • Van Geldre E, Vergauwe A, Eecdkhout EVD (1997) State of the art of the production of the antimalarial compound artemisinin in plants. Plant Mol Biol 33:199–209

    PubMed  Google Scholar 

  • Geng S, Ye HC, Li GF (2001) Effects of ipt gene expression on the physiological and chemical characteristics of Artemisia annua L. Plant Sci 160:691–698

    CAS  Google Scholar 

  • Gershenzon and Croteau (1990) Gershenzon and Croteau regulation of monoterpene biosynthesis in higher plants. Recent Adv Phytochem 24:99–160

    Google Scholar 

  • Gulati A, Bharel S, Jain SK, Abdin MZ, Srivastava PS (1996) In vitro micropropagation and flowering in Artemisia annua. J Plant Biochem Biotechnol 5:31–35

    Google Scholar 

  • Guo C, Liu CZ, Ye HC, Li GF (2004) Effect of temperature on growth and artemisinin biosynthesis in hairy root cultures of Artemisia annua. Acta Bot Boreal-Occident Sin 24:1828–1831

    CAS  Google Scholar 

  • Gupta MM, Jain DC, Mathur AK, Singh AK, Verma RK (1996) Planta Med 62:280

    PubMed  CAS  Google Scholar 

  • Han JL, Wang H, Ye HC, Liu Y, Li ZQ, Zhang Y, Zhang YS, Yan F, Li GF (2005) High efficiency of genetic transformation and regeneration of Artemisia annua L. via Agrobacterium tumefaciens-mediated procedure. Plant Sci 168:73–80

    CAS  Google Scholar 

  • Han JL, Liu BY, Ye HC, Wang H, Li ZQ, Li GF (2006) Effects of overexpression of the endogenous farnesyl diphosphate synthesis on the artemisinin content in Artemisia annua L. J Integr Palnt Biol 48(4):482–487

    CAS  Google Scholar 

  • Hardoim PR, van Overbeek LS, van Elsas JD (2008) Properties of bacterial endophytes and their proposed role in plant growth. Trends Microbiol 16:463–471

    PubMed  CAS  Google Scholar 

  • Harker M, Bramley PM (1999) Expression of prokaryotic 1-deoxy-D-xylulose-5-phosphatases in Escherichia coli increases carotenoid and ubiquinone biosynthesis. FEBS Lett 448:115–119

    Google Scholar 

  • Haynes KA, Caudy AA, Collins L, Elgin SCR (2006) Element 1360 and RNAi components contribute to HP1-dependent silencing of a pericentric reporter. Curr Biol 16(22):2222--2227

    Google Scholar 

  • He XC, Zeng MY, Li GF, Liang Z (1983) Callus induction and regeneration of plantlets from Artemisia annua and changes of qinghaosu contents. Acta Bot Sin 25:87–90

    CAS  Google Scholar 

  • Hong GJ, Hu WL, Li JX, Chen XY, Wang LJ (2009) Increased accumulation of artemisinin and anthocyanins in Artemisia annua expressing the Arabidopsis blue light receptor CRY1. Plant Mol Biol Rep. doi:10.1007/s11105-008-0088-6

    Google Scholar 

  • Jaziri M, Shimonurec K, Yoshimatsu K, Fauconmiez ML, Marlier M, Homes J (1995) Establishment of normal and transformed root cultures of Artemisia annua L. for artemisinin production. J Plant Physiol 145:175--177

    Google Scholar 

  • Jha P, Ram M, Khan MA, Zhaffar M, Abdin MZ (2011) Impact of organic manure and chemical fertilizers on artemisinin content and yield in Artemisia annua L. Ind Crops Prod 33(2):296–301

    CAS  Google Scholar 

  • Jing F, Zhang L, Li M, Tang K (2008) Over-expressing cyp71av1 and cpr genes enhances artemisinin content in Artemisia annua L. J Agric Sci Technol 10:64–70

    Google Scholar 

  • Jung M, ElSohly HN, Mc Chesney JD (1990) Artemisinic acid: a versatile chiral synthon and bioprecursor to natural products. Planta Med 56:624

    Google Scholar 

  • Kajiwara S, Fraser PD, Kondo K, Misawa N (1997) Expression of an exogenous isopentenyl diphosphate isomerase gene enhances isoprenoid biosynthesis in Escherichia coli. Biochem J 324:421--426

    Google Scholar 

  • Kasahara H, jiao Y, Bedgar DL, Kim SJ, Patten AM, Xia ZQ, Davin LB, Lewis NG (2006) Pinus taeda phenylpropenal double-bond reductase: purification, cDNA cloning, heterologous expression in Escheria Ccoli, and subcellular localization in P. taeda. Phytochem 67:1765--1780

    Google Scholar 

  • Kapoor R, Chaudhary V, Bhatnagar AK (2007) Effects of arbuscular mycorrhiza and phosphorus application on artemisinin concentration in Artemisia annua L. Mycorrhiza 17:581–587

    PubMed  CAS  Google Scholar 

  • Kappers IF, Aharoni A, Vanherpen TWJM, Luckerhoff LLP, Dick M, Bouwmeester HJ (2005) Genetic engineering of terpenoid metabolism attracts bodyguards to Arabidopsis. Science 309:2070–2072

    PubMed  CAS  Google Scholar 

  • Kim YJ, Wyslouzil BE, Weathers PJ (2002) Secondary metabolism of hairy root cultures in bioreactors. In Vitro Cell Dev Biol Plant 38:1–10

    CAS  Google Scholar 

  • Kim SW, Keasling JD (2001) Metabolic engineering of the nonmevalonate isopentenyl diphosphate synthesis pathway in Escherichia coli enhances lycopene production. Biotechnol Bioeng 72: 408--415

    Google Scholar 

  • Kim YJ, Weathers PJ, Wyslouzil BE (2003) Growth dynamics of Artemisia annua hairy roots in three culture systems. Biotechnol Bioeng 83:428–443

    PubMed  CAS  Google Scholar 

  • Klayman DL (1989) Weeding out malaria. Nat Hist October:18–26

    Google Scholar 

  • Klayman DL (1993) Artemisia annua: from weed to respectable antimalarial plant. In: Kinghorn AD, Balandri MF (eds) Human medicinal agents from plants. American Chemical Society, Washington, DC, pp 242–255

    Google Scholar 

  • Klayman DL (1985) Qinghaosu (Artemisinin): an antimalarial drug from China. Science 228:1049–1055

    PubMed  CAS  Google Scholar 

  • Klayman DL, Lin AJ, Acton N, Scovill JP, Hock JM, Milhous WK, Theoharides AD (1984) Isolation of artemisinin (qinghaosu) from Artemisia annua growing in the United States. J Nat Prod 47:715–717

    PubMed  CAS  Google Scholar 

  • Korth KL, Jaggard DAW, Dixon RA (2000) Development and light regulated post translational control of 3-hydroxy 3-methylglutary coenzyme A reductase levels in potato. The Plant J 23:507--516

    Google Scholar 

  • Kress WJ, Wurdack KJ, Zimmer EA, Weigt LA, Janzen DH (2005) Use of DNA barcodes to identify flowering plants. Proc Natl Acad Sci USA 102:8369--8374

    Google Scholar 

  • Krishna S, Uhlemann AC, Haynes RK (2004) Artemisinins: mechanisms of action and potential for resistance. Drug Resist Updat 7:233–244

    PubMed  CAS  Google Scholar 

  • Krushkal J, Pistilli M, Ferrell KM, Souret FF, Weathers PJ (2003) Computational analysis of the evolution of the structure and function of 1-deoxy-D-xylulose-5-phosphate synthase, a key regulation of the mevalonate-independent pathway in plants. Gene 313:127--138

    Google Scholar 

  • Kudakasseril GJ, Lukem L, Stabam EJ (1987) Effect of sterol inhibitors on incorporation of 14C-isopentenyl pyrophosphate into artemisinin by a cell free system from Artemisia annua tissue culture and plants. Planta Med 53:280–284

    PubMed  CAS  Google Scholar 

  • Kumar S, Khanuja SPS, Shasany AK, Darokar MP (1999) “Jeevan Raksha” from an isolated population containing high artemisinin in foliage (0.5–1.0%). J Med Arom Plant Sci 21:47–48

    Google Scholar 

  • Laughlin JC (2002) Post-harvest drying treatment effects on antimalarial constituents of Artemisia annua L. Acta Hortic 576:315–320

    CAS  Google Scholar 

  • Laughlin JC (l994) Agricultural production of artemisinin: a review. Trans Royal Soc Trop Med Hyg 88 (Suppl.1):21–22

    Google Scholar 

  • Liersch R, Soicke H, Stehr C (1986) Formation of artemisinin in Artemisia annua during one vegetation period. Planta Med 52:387–388

    Google Scholar 

  • Li J, Zhao G-Z, Huang H-Y, Qin S, Zhu W-Y et al (2012a) Isolation and characterization of culturable endophytic actinobacteria associated with Artemisia annua L. Antonie Van Leeuwenhoek 101:515–527

    PubMed  Google Scholar 

  • Li J, Zhao G-Z, Varma A, Qin S, Xiong Z, Huang H-Y, Zhu W-Y, Zhao L-X, Xu L-H, Zhang S, Li W-J (2012b) An endophytic pseudonocardia species induces the production of artemisinin in Artemisia annua. PLoS ONE 7:e51410

    PubMed  CAS  Google Scholar 

  • Li Y, Huang H, Wu YL (2006) Qinghaosu artemisinin a fantastic antimalarial drug from a traditional Chines medicine. In: Liang X, Fang WS (ed), Medicinal Chemistry of Bioactive Natural Products. John Wiley & Sons, Inc, pp. 183--256

    Google Scholar 

  • Lindahl AL, Olsson ME, Mercke P, Tollbom O, Schelin J, Brodelius M, Brodelius PE (2006) Production of the artemisinin precursor amorpha- 4,11-diene by engineered Saccharomyces cerevisiae. Biotechnol Lett 28:571--580

    Google Scholar 

  • Liu Y, Wang H, Ye HC, Li GF (2005) Advances in the plant isoprenoid biosynthesis pathway and its metabolic engineering. J Integr Plant Biol 47:769--782

    Google Scholar 

  • Liu Y, Ye HC, Wang H, Li GF (2003) Molecular cloning, Escherichia coli expression and genomic organization of squalene synthase gene from Artemisia annua. Acta Bot Sin 45:608--613

    Google Scholar 

  • Liu C, Zhao Y, Wang Y (2006) Artemisinin: current state and perspectives for biotechnological production of an antimalarial drug. Appl Microbiol Biotechnol 72:11–20

    PubMed  CAS  Google Scholar 

  • Liu CZ, Guo C, Wang YC, Ouyang F (2002) Effect of light irradiation on hairy root growth and artemisinin biosynthesis of Artemisia annua L. Process Biochem 38:581–585

    CAS  Google Scholar 

  • Liu CZ, Wang YC, Ouyang F, Ye HC, Li GF (1999) Improvement of artemisinin accumulation in hairy root culture of Artemisia annua L. by fungal elicitor. Bioprocess Eng 20:161–164

    CAS  Google Scholar 

  • Liu CZ, Wang YC, Ouyang F, Ye HC, Li GF (1997) Production of artemisinin by hairy root culture of Artemisia annua L. Biotechnol Lett 19:927–929

    CAS  Google Scholar 

  • Liu BY, Ye HC, Li GF (1998) Studies on dynamic of growth and artemisinin biosynthesis of hairy root of Artemisia annua L. Chin J Biotechnol 14:401–404

    CAS  Google Scholar 

  • Lu S, Xu R, Jia J, Pang J, Matsuda SPT (2002) Chen, X. Cloning and functional characterization of a b-pinene synthase from Artemisia annua that shows a circadian pattern of expression. Plant Physiol 130:477-486

    Google Scholar 

  • Luo XD, Shen CC (1987) The chemistry, pharmacology and clinical application of (qinghaosu) artemisinin and its derivatives. Med Res Rev 7:29–52

    PubMed  CAS  Google Scholar 

  • Mc garry and Croteau (1995) Terpenoid metabolism. Plant Cell 7(7):1015–1026

    Google Scholar 

  • McVaugh R (1984) A descriptive account of the vascular plants of Western Mexico. In: Andersohn WR (ed.) Flora Novo-Galiciana, vol 12. Compositae. University of Michigan Press, Ann Arbor

    Google Scholar 

  • Martinez BC, Staba EJ (1988) The production of artemisinin in Artemisia annua L. tissue cultures. Adv Cell Cult 6:69–87

    CAS  Google Scholar 

  • Martin VJ, Yoshikuni Y, Keasling JD (2001) The in vivo synthesis of plant sesquiterpenes by E. coli. Biotechnol Bioeng 75:497--503

    Google Scholar 

  • Martin VJJ, Pitera DJ, Withers ST, Newman JD, Keasling JD (2003) Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol 21:796–802

    PubMed  CAS  Google Scholar 

  • Mercke P, Crock J, Croteau R, Brodelius PE (1999) Cloning, expression, and characterization of epi-cedrol synthase, a sesquiterpene cyclase from Artemisia annua L. Arch Biochem Biophys 369:213--222

    Google Scholar 

  • Mercke P, Bengtsson M, Bouwmeester HJ, Posthumus MA, Brodelius PE (2000) Molecular cloning, expression and characterization of amorpha-4, 11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L. Arch Biochem Biophys 381:173–180

    Google Scholar 

  • Mohapatra PK, Khan AM, Prakash A, Mahanta J, Srivastava VK (1996) Effect of arteether alpha/beta on uncomplicated falciparum malaria cases in Upper Assam. Ind J Med Res 104:284–287

    CAS  Google Scholar 

  • Matsushita Y, Kang WY, Charlwood BV (1996) Cloning and analysis of a cDNA encoding farnesyl diphosphate synthase from Artemisia annua. Gene 172:207–209

    PubMed  CAS  Google Scholar 

  • Moore JC, Lai H, Li J-R, Ren R-L, McDougall JA, Singh NP, Chou C-K (1995) Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett 98:83–87

    Google Scholar 

  • Morales MR, Charles DJ, Simon JE (1993) Seasonal accumulation of artemisinin in Artemisia annua L. Acta Hort 344:416–420

    Google Scholar 

  • Mueller MS, Karhagombc IB, Hirt HM, Wemakor E (2000) The potential of Artemisia annua L. as locally produced remedy for malaria in the tropics: agricultural, chemical and clinical aspects. Ethanopharmacol 73:487–493

    CAS  Google Scholar 

  • Nair MS, Acton N, Klayman DL, Kendrick K, Basile DV, Mante S (1986) Production of artemisinin in tissue cultures of Artemisia annua. J Nat Prod 49(3):504–507

    PubMed  CAS  Google Scholar 

  • Newman JD, Chappell J (1999) Isoprenoid biosynthesis in plants: Carbon partitioning within the cytoplasmic pathway. Crit Rev Biochem Mol Biol 34:95--106

    Google Scholar 

  • Newman JD, Marshall J, Chang MCY, Nowroozi F, Paradise E, Pitera D, Newman KL, Keasling JD (2006) High-level production of amorpha-4,11-diene in a two phase partitioning bioreactor of metabolically engineered Escherichia coli. Biotechnol Bioeng 95:684–691

    Google Scholar 

  • Newton P, White N (1999) Malaria: new development in treatment and prevention. Ann Rev Med 50:179–192

    PubMed  CAS  Google Scholar 

  • Paniego NB, Giulietti AM (1996) Artemisinin production by Artemisia annua L.-transformed organ cultures. Enzyme Microb Technol 18:526–530

    CAS  Google Scholar 

  • Paniego NB, Giulietti AM (1994) Artemisia annua L.: dedifferentiated and differentiated cultures. Plant Cell Tiss Organ Cult 36:163–168

    CAS  Google Scholar 

  • Picaud S, Olifsson L, Brodelius PE (2005) Expression, purification and characterization of recombinant amorpha-4,11-diene synthase from Artemisia annua L. Arch Biochem Biophys 436:215–226

    Google Scholar 

  • Ping ZQ, Chang Z, Lulu Y, Yi YR, Mei ZX, Ying H, Ling FL, Qiu YX (2008) Cloning of artemisinin biosynthetic cDNA and novel gene overexpression. Sci China Ser C-Life Sci 51:232–244

    Google Scholar 

  • Pras N, Visser JF, Batterman S, Woerdenbag HJ, Maligre TM, Lugt CB (1991) Laboratory selection of Artemisia annua L. for high artemisinin yielding types. Phytochem Anal 2:80–83

    CAS  Google Scholar 

  • Qin MB, Li GZ, Yun Y, Ye HC, Li GF (1994) Induction of hairy root from Artemisia annua with Agrobacterium rhizogenes and its culture in vitro. Acta Bot Sin 36(Suppl):165–170

    Google Scholar 

  • Ram M, Gupta MM, Dwivedi S, Kumar S (1997) Effect of plant density on the yields of artemisinin and essential oil in Artemisia annua cropped under low input cost management in North-Central India. Planta Med 63:372–374

    PubMed  CAS  Google Scholar 

  • Ram M, Khan MA, Jha P, Khan S, Kiran U, Ahmad MM, Javed S, Abdin MZ (2010) HMG-CoA reductase limits artemisinin biosynthesis and accumulation in Artemisia annua L. Plants. Acta Physiol Plant 32:859–866

    CAS  Google Scholar 

  • Ranasinghe A, Sweatlock JD, Cooks RG (1993) A rapid screening method for artemisinin and its congeners using MS/MS: search for new analogues in Artemisia annua. J Nat Prod 56:552–563

    PubMed  CAS  Google Scholar 

  • Riley EM (1995) The London School of Tropical Medicine: a new century of malarial research. Mem Inst Oswaldo Cruz 95:25–32

    Google Scholar 

  • Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MC, Withers ST, Shiba Y, Sarpong R, Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940–943

    PubMed  CAS  Google Scholar 

  • Romero MR, Effeth T, Serrano MA, Castano B, Macias RI, Briz O, Martin JJ (2005) Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an ‘in vitro’ system. Antiviral Res 68:75–83

    PubMed  CAS  Google Scholar 

  • Roth RJ, Acton N (1987) A simple conversion of artemisinic acid into artemisinin. Planta Med 53:501

    PubMed  CAS  Google Scholar 

  • Sa G, Mi M, He-chun Y, Ben-ye L, Guo-feng L, Kang C (2001) Effect of ipt gene expression on the physiological and chemical characteristices of Artemisia annua L. Plant Sci 160:691--698

    Google Scholar 

  • Sangwan RS, Agarwal K, Luthra R, Thakur RS, Sangwan NS (1993) Biotransformation of arteannuic acid into arteannuin B and artemisinin in Artemisia annua. Phytochemistry 34:1301–1302

    CAS  Google Scholar 

  • Sangwan RS, Sangwan NS, Jain DC, Kumar S, Ranade SA (1999) RAPD profile based genetic characterization of chemotypic variants of Artemisia annua L. Biochem Mol Biol Int 47(6):935–944

    PubMed  CAS  Google Scholar 

  • Satheesan J, Narayanan AK, Sakunthala M (2012) Induction of root colonization by Piriformospora indica leads to enhanced asiaticoside production in Centella asiatica. Mycorrhiza 22:195–202

    PubMed  CAS  Google Scholar 

  • Sen R, Bandyopadhyay S, Dutta A, Mandal G, Ganguly S, Saha P (2007) Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania dovani promastigotes. J Med Microbiol 56:1213–1218

    PubMed  CAS  Google Scholar 

  • Singh A, Kaul VK, Mahajan VP, Sing A, Misra LN, Thakur RS, Husain A (1986) Introduction of Artemisia annua in India and isolation of artemisinin, a promising antimalarial drug. Indian J Pharmaceut Sci 48:137–138

    CAS  Google Scholar 

  • Singh A, Vishwakarma RA, Husain A (1988) Evaluation of Artemisia annua strain for higher artemisinin production. Planta Med 54:475–477

    PubMed  CAS  Google Scholar 

  • Singh M (2000) Effect of nitrogen, phosphorus and potassium nutrition on herb, oil and artemisinin yield of Artemsia annua under semi-arid tropical condition. J Med Aro Plant Sci 22/4A:368–369

    Google Scholar 

  • Singh NP, Lai H (2001) Selective toxicity of dehydroartemisinin and holotransferrin on human breast cancer cells. Life Sci 70:49–56

    PubMed  CAS  Google Scholar 

  • Smith TC, Weathers PJ, Cheetham RC (1997) Effect of gibberellic acid on hair root cultures of Artemisia annua growth and artemisinin production. In vitro Cell Dev Biol Plant 33:75–79

    CAS  Google Scholar 

  • Srivastava NK, Sharma S (1990) Influence of micronutrient imbalance on growth and artemisinin content in Artemisia annua. Ind J Pharm Sci 52:225

    Google Scholar 

  • Shukla A, Abad Farooqi AH, Shukla YN, Sharma S (1992) Effect of tricontanol and chlormequat on growth, plant hormones and artemisinin yield in Artemisia annua L. Plant Growth Regul 11:165–171

    CAS  Google Scholar 

  • Souret FF, Weathers PJ, Wobbe KK (2002) The mevalonateindependent pathway is expressed in transformed roots of Artemisia annua and regulated by light and culture age. In Vitro Cell Dev Biol Plant 38:581–588

    CAS  Google Scholar 

  • Souret FF, Kim Y, Wyslouzil BE, Wobbe KK, Weathers PJ (2003) Scale-up of Artemisia annua L. hairy root cultures produces complex patterns of terpenoid gene expression. Biotechnol Bioeng 83:653–667

    PubMed  CAS  Google Scholar 

  • Strobel GA (2003) Endophytes as sources of bioactive products. Microbes Infect 5:535–544

    PubMed  CAS  Google Scholar 

  • Sy LK, Brown GD (2002) The mechanism of the spontaneous autoxidation of dihydroartemisinic acid. Tetrahedron 58:897--908

    Google Scholar 

  • Tawfiq NK, Anderson LA, Roberts MF, Phillipson JD, Bray DH, Warhurst DC (1989) Antiplasmodial activity of Artemisia annua plant cell cultures. Plant Cell Rep 8:425–428

    PubMed  CAS  Google Scholar 

  • Tazyeen N, Akmal M, Ram M, Alam P, Ahlawat S, Anis M, Abdin MZ (2010) Enhancement of artemisinin content by constitutive expression of HMG-CoA reductase gene in high yielding strain of Artemisia annua L. doi:10.1007/s11816-010-0156-x

  • Teo CKH, Yap AW, Chan KL, Gan EK, Tanaka M (1995) Artemisinin production from callus of Artemisia annua cultured in fluorocarbon polymer film culture bag. Asia-Pac J Mol Biol Biotechnol 3:317–321

    Google Scholar 

  • Teoh KH, Polichuk DR, Reed DW, Nowak G, Covello PS (2006) 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 580:1411–1416

    Google Scholar 

  • Towler MJ, Weathers PJ (2007) Evidence of artemisinin production from IPP stemming from both mevalonate and nonmevalanate pathways. Plant Cell Rep 26:2129--2136

    Google Scholar 

  • Trigg PL (1990) Qinghaosu as an antimalarial drug. Econ Med Plant Res 3:20–25

    Google Scholar 

  • Utzinger J, Xiao S, N’Goran EK, Berquist R, Tanner M (2001) The potential of artemether for the control of shistosomiasis. Int J Parasitol 31:1549–1562

    PubMed  CAS  Google Scholar 

  • Van Agtmael MA, Eggetle TA, Van Boxtel CJ (1999) Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. Trends Pharmacol Sci 20:199–204

    PubMed  Google Scholar 

  • van Geldre E, De Pauw I, Inze D, Van Montagu M, Van den Eeckhout E (2000) Cloning and molecular analysis of two new sesquiterpene cyclises from Artemisia annua L. Plant Sci 158:163--171

    Google Scholar 

  • Van Wees SCM, Van der Ent S, Pieterse CMJ (2008) Plant immune responses triggered by beneficial microbes. Curr Opin Plant Biol 11:443–448

    PubMed  Google Scholar 

  • Varma A, Bakshi M, Lou B, Hartmann A, Oelmueller R (2012) Piriformospora indica: a novel plant growth-promoting Mycorrhizal Fungus. Agric Res 1:117–131

    Google Scholar 

  • Vergauwe A, Cammaert R, Vandenberghe D, Genetello C, Van Montagu M, Vanden Eeckhout E (1996) Agrobacterium tumefaciens-mediated transformation of Artemisia annua L. and regeneration of transgenic plant. Plant Cell Rep 15:929–937

    PubMed  CAS  Google Scholar 

  • Vergauwe A, Van GE, Inze D, Van DEE (1998) Factor influencing Agrobacterium tumefaciens-mediated transformation of Artemisia annua L. Plant Cell Rep 18:105–110

    CAS  Google Scholar 

  • Wallaart TE, Van Uden W, Lubberink HG, Woerdenbag HJ, Pras N, Quax WJ (1999a) Isolation and identification of dihydroartemisinic acid from Artemisia annua and its possible role in the biosynthesis of artemisinin. J Nat Prod 62:430–433

    PubMed  CAS  Google Scholar 

  • Wallaart TE, Van Uden W, Lubberink HG, Woerdenbag HJ, Pras N, Quax WJ (1999b) Isolation and identification of dihydroartemisinic acid from Artemisia annua: a novel biosynthetic precursor of artemisinin. J Nat Prod 62:1160–1162

    PubMed  CAS  Google Scholar 

  • Wallaart TE, Pras N, Beekman AC, Quax WJ (2000) Seasonal variation of artemisinin and its biosynthetic precursors in plants of Artemisia annua of different geographical origin: proof for the existence of chemotypes. Plant Med 66:57–62

    Google Scholar 

  • Wallaart TE, Boumeester HJ, Hille J, Poppinga L, Maijers NCA (2001) Amorpha-4,11-diene synthase: cloning and functional expression of a key enzyme in the biosynthetic pathway of the novel antimalarial drug artemisinin. Planta 212:460–465

    PubMed  CAS  Google Scholar 

  • Wang CW (1961) The forests of China, with a survey of grassland and desert vegetations. In: Harvard University Maria Moors Cabot Foundation No. 5. Harvard University Press, Cambridge, MA, pp 171–187

    Google Scholar 

  • Wang JW, Tan RX (2002) Artemisinin production in Artemisia annua hairy root cultures with improved growth by altering the nitrogen source of the medium. Biotechnol Lett 24:1153–1156

    CAS  Google Scholar 

  • Wang JW, Zhang Z, Tan X (2001) Stimulation of artemisinin production in Artemisia annua hairy roots by the elicitor from the endophytic Colletotrichum sp. Biotechnol Lett 23:857–860

    CAS  Google Scholar 

  • Wang H, Ye HC, Li GF, Liu BY, Chong K (2000) Effects of fungal elicitors on cell growth and artemisinin accumulation in hairy root cultures of Artemisia annua. Acta Bot Sinica 42:905–909

    CAS  Google Scholar 

  • Weathers P, Elkholy S, Wobbe KK (2006) Invited review: Artemisinin: The biosynthetic pathway and its regulation in Artemisia annua, a terpenoid-rich species. In Vitro Cell Dev Biol—Plant 42:309--317

    Google Scholar 

  • Weathers PJ, Cheetham RD, Follansbee E, Tesh K (1994) Artemisinin production by transformed roots of Artemisia annua. Biotech Lett 16:1281–1286

    CAS  Google Scholar 

  • Weathers PJ, Bunk G, Mccoy MC (2005) The effect of phytohormones on growth and artemisinin production in Artemisia annua hairy roots. In Vitro Cell Dev Biol Plant 41:47–53

    CAS  Google Scholar 

  • Weathers PJ, DeJesus-Gonzalez L, Kim YJ (2004) Alteration of biomass and artemisinin production in Artemisia annua hairy roots by media sterilization method and sugars. Plant Cell Rep 23:414–418

    PubMed  CAS  Google Scholar 

  • Whipkey A, Simon JE, Charles DJ, Janick J (1992) In vitro production of artemisinin from Artemisia annua L. Phytother Res 1:15–25

    Google Scholar 

  • Woerdenbag HJ, Lüers JFJ, van Uden W, Pras N, Malingré TM, Alfermann AW (1993) Production of the new antimalarial drug artemisinin in shoot cultures of Artemisia annua L. Plant Cell Tiss Org Cult 32:247–257

    CAS  Google Scholar 

  • World Bank (2003) Expert Consultation on the Procurement & Financing of Antimalarial Drugs. Meeting Report, Draft 3. World Bank, Washington, DC, 7 Nov 2003

    Google Scholar 

  • Xie DY, Wang LH, Ye HC, Li GF (2000) Isolation and production of artemisinin and stigmasterol in hairy root cultures of Artemisia annua. Plant Cell Tiss Org Cult 63:161–166

    CAS  Google Scholar 

  • Xie DY, Zou ZR, Ye HC, Li GF, Guo ZC (2001) Selection of hairy root clones of Artemisia annua L. for artemisinin production. Isr J Plant Sci 49:129–134

    CAS  Google Scholar 

  • Xu XX, Zhu J, Huang DZ, Zhou WS (1986) Total synthesis of arteannuin and deoxyarteannuin. Tetrahedron 42:819–828

    CAS  Google Scholar 

  • Yaseen M, Tajuddin (1998) Effect of plant growth regulators on yield, oil composition and artemisinin from Artemisia annua under temperate condition. J Med Aromat Plant Sci 20:1038–1041

    Google Scholar 

  • Yuan ZL, Dai CC, Chen LQ (2007) Regulation and accumulation of secondary metabolites in plant-fungus symbiotic system. Afr J Biotechnol 6:1266–1271

    CAS  Google Scholar 

  • Zeng QP, Qiu F, Yuan L (2007) Production of artemisinin by genetically modified microbes. Biotechnol Lett. doi:10.1007/s10529-007-9596-y

  • Zhang L, Ye H, Li G (2006) Effect of development stage on the artemisinin content and the sequence characterized amplified region (SCAR) markers of high-artemisinin yielding strains of Artemisia annua L. J Intg Plant Biol 48:1054–1062

    CAS  Google Scholar 

  • Zhang L, Jing F, Li F, Li M, Wang Y, Wang G, Sun X, Tang K (2009) 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 52:199–207

    PubMed  CAS  Google Scholar 

  • Zhang YS, Liu B Y, Li ZQ, Ye HC, Wang HL, Guo-Feng HJL (2004) Molecular cloning of a classical plant peroxidase from Artemisia annua and its effect on the biosynthesis of artemisinin in vitro. Acta Bot Sin 46:1338--1346

    Google Scholar 

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Authors and Affiliations

  1. Department of Greentechnology, Ipca Laboratories Ltd, Sejavta, Ratlam, 457002,, Madhya Pradesh, India

    Mauji Ram, D. C. Jain & Himanshu Mishra

  2. Department of Botany, Faculty of Science, Delhi University, New Delhi, 110007, India

    Shantanu Mandal

  3. Department of Biotechnology, Faculty of Science, Jamia Hamdard, New Delhi, 110062, India

    M. Z. Abdin

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  1. Mauji Ram
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  2. D. C. Jain
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  3. Himanshu Mishra
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  4. Shantanu Mandal
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  5. M. Z. Abdin
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Correspondence to Mauji Ram .

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  1. Department of Physiology and Cell Biology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany

    Tariq Aftab

  2. US Salinity Laboratory, United States Department of Agriculture Agriculture Research Service, Riverside, California, USA

    Jorge F.S. Ferreira

  3. Botany Department, Aligarh Muslim University, Aligarh, India

    M. Masroor A. Khan

  4. Botany Department, Aligarh Muslim University, Aligarh, India

    M. Naeem

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Ram, M., Jain, D.C., Mishra, H., Mandal, S., Abdin, M.Z. (2014). Recent Advances to Enhance Yield of Artemisinin: A Novel Antimalarial Compound, in Artemisia annua L. Plants. In: Aftab, T., Ferreira, J., Khan, M., Naeem, M. (eds) Artemisia annua - Pharmacology and Biotechnology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-41027-7_11

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