SpringerLink
Log in

Genetic engineering of artemisinin biosynthesis: prospects to improve its production

  • Review
  • Published:
Acta Physiologiae Plantarum Aims and scope Submit manuscript

Abstract

Key massage

Approaches involved in production of Artemisinin in different hosts.

Abstract

Artemisinin, a potent antimalarial natural compound, is obtained from aerial parts of Artemisia annua L. plants. The demand (101–119 MT) for artemisinin is exponentially increasing every year because of increased incidence of drug-resistant malaria throughout the world, especially in Africa and Asia. However, the presence of low concentrations (0.01–1.1 %) of the compound in A. annua L. plants poses a major constraint in the commercialization of artemisinin-based combination therapies (ACTs) recommended by WHO for the treatment of multidrug-resistant and cerebral malaria. Further, the improvement in the yield of artemisinin through conventional breeding, in vitro culture, cell suspension culture and total organic synthesis still poses a challenge. However, possibilities are there to enhance the artemisinin biosynthesis either by overexpression of the genes encoding enzymes associated with the rate-limiting steps of the mevalonate and artemisinin biosynthetic pathways or by the suppression of genes encoding enzymes of other competing pathways. Based on the current understanding of the pathway and cloning of the related genes, efforts have been made for the past few years to increase the artemisinin content in A. annua L., Cichorium intybus L. and microbes through metabolic engineering. In the present review, we have discussed the metabolic engineering strategies in both plant and microbial systems for artemisinin accumulation in bioengineered hosts.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ACTs:

Artemisinin-based combined therapies

mtADS:

Mitochondrial amorpha 4,11-diene synthase

HMG:

HMG CoA reductase

IPP:

Isopentenyl pyrophosphate

IPT:

Isopentenyl transferase

DMAP:

Dimethylallyl pyrophosphate

MVA:

Meavalonate Pathway

MEP:

Methylerythritol Phosphate (non-mevalonate) Pathway

CPS:

Caryophyllene synthase

ERG:

Ergosterol

hpRNAi:

Hairpin loop RNA interferance

ABA:

Abscisic Acid

DBR2:

Double bond reducatse

PMET3:

Methionine-repressible promoter

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

    Article  CAS  PubMed  Google Scholar 

  • Ahlawat S, Saxena P, Alam P, Mauji Ram, Nafis T, Mohd A, Abdin MZ (2012) Influence of Agrobacterium rhizogenes on induction of hairy roots for enhanced production of artemisinin in Artemisia annua L. plants. Afr J Biotecnol 1:8684–8691

    Google Scholar 

  • Akhila A, Kumkum R, Thakur RS (1999) Biosynthesis of artemisinic acid in Artemisia annua. Phytochemistry 29:2129–2132

    Article  Google Scholar 

  • Akiyoshi DE, Morris RO, Hinz R, Mischke BS, Kosuge T, Garfinkel DJ, Gordon MP, Nester EW (1983) Cytokinin/auxin balance in crown gall tumors is regulated by specific loci in the T-DNA. Proc Natl Acad Sci USA 80(2):407–411

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Alam, P, Kamaluddin, Khan MA, Mohammad A, Khan R, Abdin MZ (2014) Enhanced artemisinin accumulation and metabolic profiling of transgenic Artemisia annua L. plants over-expressing by rate limiting enzymes from isoprenoid pathway, J Plant Inter. doi:10.1080/17429145.2014.893030

  • Alam P, Abdin MZ (2011) Over-expression of HMG-CoA reductase and amorpha-4,11-diene synthase genes in Artemisia annua L. and its influence on artemisinin content. Plant Cell Rep 10:1919–1928

    Article  Google Scholar 

  • Alam P, Kiran U, Ahmad MM, Kamaluddin Khan MA, Jhanwar S, Abdin MZ (2010) Isolation, characterization and structural features of amorpha—4,11-diene synthase (ADS3963) from Artemisia annua L. Bioinformation 4:421–429

    Article  PubMed Central  PubMed  Google Scholar 

  • Allen RS, Millgate AG, Chitty JA, Thisleton J, Miller JA, Fist AJ, Gerlach WL, Larkin PJ (2004) RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy. Nat Biotechnol 22(12):1559–1566

    Article  CAS  PubMed  Google Scholar 

  • Anthony JR, Anthony LC, Nowroozi F, Kwon G, Newman JD, Keasling JD (2009) 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 11:13–19

    Article  CAS  PubMed  Google Scholar 

  • Aquil S, Husaini AM, Abdin MZ, Rather GM (2009) Overexpression of the HMG-CoA Reductase Gene Leads to Enhanced Artemisinin Biosynthesis in transgenic Artemisia annua Plants. Planta Med 75:1–6

    Article  Google Scholar 

  • Arsenault PR, Wobbe KK, Weathers PJ (2008) Recent advances in artemisinin production through heterologous expression. Curr Med Chem 15:2886

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Arsenault PR, Vail DR, Wobbe KK, Erickson K, Weathers PJ (2010) Reproductive development modulates gene expression and metabolite levels with possible feedback inhibition of artemisinin in A. annua L. Plant Physiol 154:958–968

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Attucci S, Aitken SM, Gulick PJ, Ibrahim RK (1995) Farnesyl pyrophosphate synthase from white lupin: molecular cloning, expression, and purification of the expressed protein. Arch Biochem Biophys 321(2):493–500

    Article  CAS  PubMed  Google Scholar 

  • 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 Tissue Organ. 103:255–265

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bharel S, Gulati A, Abdin MZ, Srivastava PS, Vishwakarma RA, Jain SK (1998) Enzymatic synthesis of artemisinin from natural and synthetic precursors. J Nat Prod 61:633–636

    Article  CAS  PubMed  Google Scholar 

  • Brown GD (2010) The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao). Molecules 15:7603–7698

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Chang MCY, Eachus RA, Trieu W, Ro DK, Keasling JD (2007) Engineering Escherichia coli for production of functionalized terpenoids using plant P450s. Nat Chem Biol 3:274–277

    Article  CAS  PubMed  Google Scholar 

  • Chen DH, Liu CJ, Ye HC, Li GF, Liu BY, Meng YL, Chen XY (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

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Chen JL, Fang HM, Ji YP, Pu GB, Guo YW, Huang LL, Du ZG, Liu BY, Ye HC, Li GF, Wang H (2011) Artemisinin biosynthesis enhancement in transgenic Artemisia annua plants by downregulation of the β-caryophyllene synthase gene. Planta Med. doi:10.1055/s-0030-1271038

    Google Scholar 

  • Covello PS (2008) Making artemisinin. Phytochemistry 69(17):2881–2885

    Article  CAS  PubMed  Google Scholar 

  • De Kraker JW, Scurink M, Franssen MCR, Konig WA, de Groot A, Bouwmeester HJ (2003) Hydroxylation of sesquiterpenes by enzymes from chicory (Cichorium intybus L.) roots. Tetrahedron 59:409–418

    Article  Google Scholar 

  • Delabays N, Benakis A, Collet G (1993) Selection and breeding for high artemisinin (Qinghaosu) yielding strains of Artemisia annua. Acta Hort (ISHS). 330:203–208

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Delabays N, Darbellay C, Galland N (2002) Variation and heritability of artemisinin content in Artemisia annua L. In: Wright CW (ed) Artemisia. Taylor & Francis, London, pp 197404–209999

    Google Scholar 

  • Delourme D, Lacroute F, Karst F (1994) Cloning of an Arabidopsis thaliana cDNA coding for farnesyl diphosphate synthase by functional complementation in yeast. Plant Mol Biol 26(6):1867–1873

    Article  CAS  PubMed  Google Scholar 

  • Duffy PE, Mutabingwa TK (2006) Artemisinin combination therapies. Lancet 367:2037–2039

    Article  PubMed  Google Scholar 

  • Elfawal MA, Towler MJ, Reich NG, Golenbock D, Weathers PJ, Rich SM (2013) Dried whole plant Artemisia annua as an antimalarial therapy. PLoS One 7:e52746. doi:10.1371/journal.pone.0061989

    Article  Google Scholar 

  • Farhi M, Marhevka E, Ben-Ari J, Algamas-Dimantov A, Liang Z, Zeevi V, Edelbaum O, Spitzer-Rimon B, Abeliovich H, Schwartz B, Tzfira T, Vainstein A (2011) Generation of the potent anti-malarial drug artemisinin in tobacco. Nat Biotechnol 29(12):1072–1074

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Graham IA, Besser K, Blumer S, Branigan CA, Czechowski T, Elias L, Guterman I, Harvey D, Isaac PG, Khan AM, Larson TR, Li Y, Pawson T, Penfield T, Rae AM, Rathbone DA, Reid S, Ross J et al (2010) The genetic map of Artemisia annua L. identifies loci affecting yield of the antimalarial drug artemisinin. Science 327:328–331

    Article  CAS  PubMed  Google Scholar 

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

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Hong GJ, Hu WL, Li JX, Chen XY, Wang LJ (2009) Increased accumulation of artemisinin anthocyanins in Artemisia annua expressing the Arabidopsis blue light receptor CRY1. Plant Mol Biol Rep. doi:10.1007/S11105-008-0088-6

    Google Scholar 

  • Jain DC, Mathur AK, Gupta MM, Singh AK, Verma RK, Gupta AP, Kumar S (1996) Isolation of high artemisinin-yielding clones of Artemisia annua. Phytochemistry 6(5):993–1001

    Article  Google Scholar 

  • **g FY, Zhang L, Li MY, Tang KX (2008) Over-expressing cyp71avl and cpr genes enhances artemisinin content in Artemisa annua L. J Agr Sci Tech Iran 10(3):64–70

    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

    PubMed Central  CAS  PubMed  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. Plant J 23:507–516

    Article  CAS  PubMed  Google Scholar 

  • Kudakasseril GJ, Lam L, Staba EJ (1987) Effect of sterol inhibitors on the incorporation of 14C-isopentylpyrophosphate into artemisinin by a cell-free system from Artemisia annua tissue cultures and plants. Planta Med 53:280–284

    Article  CAS  PubMed  Google Scholar 

  • Lenihan JR, Tsuruta H, Diola D, Renninger NS, Regentin R (2008) Develo** an industrial artemisinic acid fermentation process to support the cost-effective production of antimalarial artemisinin-based combination therapies. Biotechnol Prog 24:1026–1032

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Huang H, Wu YL (2006) Ginghaosu (artemisinin)—a fantastic antimalarial drug from a traditional Chinese medicine. In: Liang X-T, Fang WS (Eds.) Medicinal chemistry of bioactive natural products. Wiley Interscience, Hoboken, pp 183–256

  • Liu J, Ni M, Fan J, Tu Y, Wu Z, Wu Y, Zhou W (1979) Structure and reaction of Qinghaosu (in Chinese). Acta Chim Sinica 37:129–143

    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

    Article  CAS  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

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Liu B, Wang H, Du Z, Li G, Ye H (2011) Metabolic engineering of artemisinin biosynthesis in Artemisia annua L. Plant Cell Rep 30(5):689–694

    Article  CAS  PubMed  Google Scholar 

  • Ma C, Wang H, Lu X, Xu G, Liu B (2008) Metabolic fingerprinting investigation of Artemisia annua L. in different stages of development by gas chromatography and gas chromatography–mass spectrometry. J Chromatogr A 1186:412–419

    Article  CAS  PubMed  Google Scholar 

  • Ma C, Wang HH, Lu X, Wang H, Xu G, Liu B (2009a) Terpenoid metabolic profiling analysis of transgenic Artemisia annua L. by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. Metabolomics 5:497–506

    Article  CAS  Google Scholar 

  • Ma D, Pu G, Lei C, Ma L, Wang H, Guo Y, Chen J, Du Z, Li G, Ye H, Liu B (2009b) Isolation and characterization of AaWRKY1, an Artemisia annua transcription factor that regulates the amorpha- 4,11-diene synthase gene, a key gene of artemisinin biosynthesis. Plant Cell Physiol 50:2146–2161

    Article  CAS  PubMed  Google Scholar 

  • Maes L, Van Nieuwerburgh FCW, Zhang YS, Reed DW, Pollier J, Casteele S, Inze D, Covello PS, Deforce DLD, Goossens A (2011) Dissection of the phytohormonal regulation of trichome formation and biosynthesis of the antimalarial compound artemisinin in Artemisia annua plants. New Phytol 189:176–189

    Article  CAS  PubMed  Google Scholar 

  • Martin VJJ, Pitera DJ, Withers ST, Newman JD, Keasling JD (2003) Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nature Biotech 7:796–802

    Article  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

    Article  CAS  PubMed  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

    Article  CAS  PubMed  Google Scholar 

  • Nafis T, Akmal M, Mauji Ram, Alam P, Ahlawat S, Mohammad A, Abdin MZ (2011) Enhancement of artemisinin content by constitutive expression of HMG CoA Reductase gene in high yielding strain of Artemisia annua L. Plant Biotechnol Rep. 5:53–60

    Article  Google Scholar 

  • Nair MSR, Basile DV (1993) Bioconversion of arteannuin B to artemisinin. J Nat Prod 56:1559–1566

    Article  CAS  PubMed  Google Scholar 

  • Nair P, Misra A, Singh A, Shukla AK, Gupta MM et al (2013) Differentially expressed genes during contrasting growth stages of Artemisia annua for artemisinin content. PLoS ONE 8(4):e60375. doi:10.1371/journal.pone.0060375

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nguyen KT, Arsenault PR, Weathers PJ (2011) Trichomes +roots + ROS = artemisinin: regulating artemisinin biosynthesis in Artemisia annua L. In Vitro Cell Dev Biol Plant 47:329–338

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ogita S, Uefuji H, Morimoto M, Sano H (2004) Application of RNAi to confirm theobromine as the major intermediate for caffeine biosynthesis in coffee plants with potential for construction of decaffeinated varieties. Plant Mol Biol 54(6):931–941

    Article  CAS  PubMed  Google Scholar 

  • Olsson ME, Olofsson LM, Lindahl AL, Lundgren A, Brodelius M, Brodelius PE (2009) Localization of enzymes of artemisinin biosynthesis to the apical cells of glandular secretory trichomes of Artemisia annua L. Phytochemistry 70:1123–1128

    Article  CAS  PubMed  Google Scholar 

  • Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D, Leavell MD, Tai A, Main A, Eng D, Polichuk DR et al (2013) High-level semisynthetic production of the potent antimalarial artemisinin. Nature 496:528–532

    Article  CAS  PubMed  Google Scholar 

  • Paul S, Khanuja SP, Shasany AK, Gupta MM, Darokar MP, Saikia D, Gupta AK (2010) Enhancement of artemisinin content through four cycles of recurrent selection with relation to heritability, correlation and molecular marker in Artemisia annua L. Planta Med 76:1468–1472

    Article  CAS  PubMed  Google Scholar 

  • MaujiRam, 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

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Rydén AM, Ruyter-Spira C, Quax WJ, Osada H, Muranaka T, Kayser O, Bouwmeester H (2010) The molecular cloning of dihydroartemisinic aldehyde reductase and its implication in artemisinin biosynthesis in Artemisia annua. Planta Med 76(15):1778–1783

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Schramek N, Wang H, Romisch-Margl W, Keil B, Radykewicz T, Winzenhorlein B, Beerhues L, Bacher A, Rohdich F, Gershenzon J, Liu B, Eisenreich W (2010) Artemisinin biosynthesis in growing plants of Artemisia annua. A 13CO2 study. Phytochemistry 71:179–187

    Article  CAS  PubMed  Google Scholar 

  • Shen Q, Chen YF, Wang T, Wu SY, Lu X, Zhang L, Zhang FY, Jiang WM, Wang GF, Tang KX (2012) Overexpression of the cytochrome P450 monooxygenase (cyp71av1) and cytochrome P450 reductase (cpr) genes increased artemisinin content in Artemisia annua (Asteraceae). Genet Mol Res 11:3298–3309

    Article  CAS  PubMed  Google Scholar 

  • Tang KX, Shen Q, Chen YF, Wang T, Wu SY, Lu X (2012b) Overexpression DBR2 gene increased artemisinin content in Artemisia annua L. Shanghai Jiao Tong University, China. Patent CN201210014227.2

  • Tang KX, Chen YF, Shen Q, Wang T, Wu SY, Wang GF (2012c) Overexpression ALDH1 gene increased artemisinin content in Artemisia annua L. Shanghai Jiao Tong University, China. Patent CN201210014242.7

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Teoh KH, Polichuk DR, Reed DW, Nowak G, Covello PS (2009) Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annua. Botany. 87:635–642

    Article  CAS  Google Scholar 

  • Towler MJ, Weathers PJ (2007) Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways. Plant Cell Rep 26(12):2129–2136

    Article  CAS  PubMed  Google Scholar 

  • Townsend T, Segura V, Chigeza G, Penfield T, Rae A, Harvey D, Bowles D, Graham IA (2013) The use of combining ability analysis to identify elite parents for Artemisia annua F1 hybrid production. PLoS One 8(4):e61989. doi:10.1371/journal.pone.0061989

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tsuruta H, Paddon CJ, Eng D, Lenihan JR, Horning T, Anthony LC, Regentin R, Keasling JD, Renninger NS, Newman JD (2009) High-level production of amorpha-4,11-diene, a precursor of the antimalarial agent artemisinin, in Escherichia coli. PLoS One 4:e4489

    Article  PubMed Central  PubMed  Google Scholar 

  • Wallaart TE, Bouwmeester HJ, Hille J, Pop**a L, Maijers NC (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

    Article  CAS  PubMed  Google Scholar 

  • Wang YY, **g FY, Yu SY, Chen YF, Wang T, Liu P, Wang GF, Sun XF, Tang KX (2011a) Co-overexpression of the HMGR and FPS genes enhances artemisinin content in Artemisia annua L. J Med Plants Res 5:3396–3403

    CAS  Google Scholar 

  • Wang YY, Yang K, Deng T, Huang R, Wang B, Wang GF, Sun XF, Tang KX (2011b) Cloning and characterization of trichome specific promoter of cpr71av1 gene involved in artemisinin biosynthesis in Artemisia annua L. Mol Biol 145:751–758

    Article  Google Scholar 

  • Wang HZ, Han JL, Kanagarajan S, Lundgren A, Brodelius PE (2013) Trichome-specific expression of the amorpha-4,11-diene 12-hydroxylase (cyp71av1) gene, encoding a key enzyme of artemisinin biosynthesis in Artemisia annua, as reported by a promoter-GUS fusion. Plant Mol Biol 81:119–138

    Article  CAS  PubMed  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

    Article  CAS  Google Scholar 

  • Weathers PJ, Jordan NJ, Lasin P, Towler MJ (2014) Simulated digestion of dried leaves of Artemisia annua consumed as a treatment (pACT) for malaria. J Ethnopharmacol 151(2):858–863

    Article  PubMed Central  PubMed  Google Scholar 

  • Westfall PJ, Pitera DJ, Lenihan JR, Eng D, Woolard FX, Regentin R, Horning T, Tsuruta H, Melis DJ, Owens A, Fickes S, Diola D, Benjamin KR, Keasling JD, Leavell MD, McPhee DJ, Renninger NS, Newman JD, Paddon CJ (2012) Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. Proc Natl Acad Sci 109:E111–E118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • White NJ (2008) Qinghaosu (artemisinin): the price of success. Science 320:330–334

    Article  CAS  PubMed  Google Scholar 

  • Woerdenbag HJ, Jos FJ, van Uden W, Pras N, Malingre TM, Alfermann AW (1993) Production of the new antimalarial drug artemisinin in shoot cultures of Artemisia annua L. Plant Cell, Tissue Organ Cult 32:247–257

    Article  CAS  Google Scholar 

  • **ang LE, Zeng LX, Yuan Y, Chen M, Wang F, Liu XQ, Zeng LJ, Lan XZ, Liao ZH (2012) Enhancement of artemisinin biosynthesis by overexpressing dxr, cyp71av1 and cpr in the plants of Artemisia annua L. Plant Omics J 5:503–507

    CAS  Google Scholar 

  • Yu ZX, Li JX, Yang CQ, Hu WL, Wang LJ, Chen XY (2012) The jasmonate-responsive AP2/ERF transcription factors AaERF1 and AaERF2 positively regulate artemisinin biosynthesis in Artemisia annua L. Mol Plant 5(2):353–365

    Article  CAS  PubMed  Google Scholar 

  • Zhang YS, Teoh KH, Reed DW, Maes L, Goossens A, Olson DJ, Ross ARS, Covello PS (2008) The Molecular Cloning of Artemisinic Aldehyde 1–1(13) reductase and Its Role in Glandular Trichome-dependent Biosynthesis of Artemisinin in Artemisia annua. J Bio Chem 283:21501–21508

    Article  CAS  Google Scholar 

  • Zhang L, **g 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

    Article  CAS  PubMed  Google Scholar 

  • Zhang F, Lu X, Lv Z, Zhang L, Zhu M, Jiang W, Wang G, Sun X, Tang K (2013) Overexpression of the Artemisia orthologue of ABA receptor, AaPYL9, enhances ABA sensitivity and improves artemisinin content in Artemisia annua L. PLoS One 8(2):e56697

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu C, Cook SP (2012) A concise synthesis of (?)—artemisinin. J Am Chem Soc 134:13577–13579

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

P. A. is thankful to Jamia Hamdard and Department of Science and Technology, Government of India, New Delhi, India and university grant commission for providing Dr. D. S. Kothari Post Doctoral Fellowship. The financial support as project grant from DST, Government of India and M/s Ipca Pvt. Ltd., Mumbai, India to MZA is gratefully acknowledged. We are also thankful to Dr. M. A. A. Khan, Scientist, National Institute of Science Communication and Information Resources (NISCARE) CSIR, Government of India for critically editing this manuscript and UGC for providing UGC-SAP grant to the Department of Biotechnology, Jamia Hamdard, New Delhi.

Conflict of interest

No conflict of interest between the authors.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biotechnology, Centre for Transgenic Plant Development, Jamia Hamdard, New Delhi, 110062, India

      Malik Zainul Abdin

    2. Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India

      Pravej Alam

    Authors
    1. Malik Zainul Abdin
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Pravej Alam
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Malik Zainul Abdin.

    Additional information

    Communicated by A. K. Kononowicz.

    M. Z. Abdin and P. Alam contributed equally.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Abdin, M.Z., Alam, P. Genetic engineering of artemisinin biosynthesis: prospects to improve its production. Acta Physiol Plant 37, 33 (2015). https://doi.org/10.1007/s11738-015-1771-5

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • DOI: https://doi.org/10.1007/s11738-015-1771-5

    Keywords

    Search

    Navigation