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DOI: 10.1055/s-2003-38871
Artemisinin, a Novel Antimalarial Drug: Biochemical and Molecular Approaches for Enhanced Production
Publication History
Received: July 2, 2002
Accepted: November 16, 2002
Publication Date:
23 April 2003 (online)
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Abstract
Artemisinin, a sesquiterpene lactone containing an endoperoxide bridge, has been isolated from the aerial parts of Artemisia annua L. plants. It is effective against both drug-resistant and cerebral malaria-causing strains of Plasmodium falciparum. The relatively low yield (0.01 - 0.8 %) of artemisinin in A. annua is a serious limitation to the commercialization of the drug. Therefore, the enhanced production of artemisinin either in cell/tissue culture or in the whole plant of A. annua is highly desirable. It can be achieved by a better understanding of the biochemical pathway leading to the synthesis of artemisinin and its regulation by both exogenous and endogenous factors. Furthermore, genetic engineering tools can be employed to overexpress gene(s) coding for enzyme(s) associated with the rate limiting step(s) of artemisinin biosynthesis or to inhibit the enzyme(s) of other pathway competing for its precursors. These aspects which may be employed to enhance the yield of artemisinin both in vitro and in vivo are discussed in this review.
Key words
Artemisinin - Artemisia annua - Asteraceae - tissue culture - biotransformation - antimalarial drug
References
- 1 WHO . UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (1994 - 1995). The role of artemisinin and its derivatives in the current treatment of malaria. Report of an informal Consultation convened by WHO in Geneva 27 - 29 September 1993
- 2 Wernsdorfer W H. Epidemiology of drug resistance in malaria. Acta Trop. 1994; 56 143-56
- 3 Gray A. Synoptical flora of North America. Vol. 1, Part II Smithsonian Institution, Washington DC Univ. Press, John Wilson and Son Cambridge; 1984
- 4 Klayman D L. Qinghaosu (artemisinin): An antimalarial drug from China. Science. 1985; 228 1049-54
-
5 Klayman D L.
A. annua: from weed to respectable antimalarial plant. In: Kinghorm AD, Balandrin MF, editors
Human Medicinal Agents from Plants . American Chemical Society Symposium Series, ACS Washington DC; 1993: 242-55 - 6 Trigg P I. Qinghaosu (artemisinin) as an antimalarial drug. Econ Med Plant Res. 1990; 3 20-55
- 7 Anonymous . Qinghaosu Antimalarial Coordinating Research Group. Antimalarial studies on Qinghaosu. Chin Med J. 1979; 92 811-6
- 8 Van Agtmael M A, Eggelte T A, van Boxtel C J. Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. Trends Pharmacol Sci. 1999; 20 199-204
- 9 Avery M A, Chong W KM, Jennings-White C. Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L. J Am Chem Soc. 1992; 114 974-9
- 10 Roth R J, Acton N A. A simple conversion of artemisinic acid into artemisinin. J Nat Prod. 1989; 52 1183-5
- 11 Schmid G, Hofheinz W. Total synthesis of qinghaosu. J Am Chem Soc. 1983; 105 624-5
- 12 Xu X X, Zhu J, Huang D Z, Zhou W S. Total synthesis of arteannuin and deoxyarteannuin. Tetrahedron. 1986; 42 819-28
- 13 Ravindranathan T, Anil Kumar M, Menon R B, Hiremath S V. Stereoselective synthesis of artemisinin. Tetrahedron Lett. 1990; 31 755-8
- 14 Laughlin J C. Agricultural production of artemisinin: a review. Trans Royal Soc Trop Med Hyg. 1994; 88 ( 1) 21-32
- 15 UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases ( 1981). Report of a meeting of the Scientific Working Group on the chemotherapy of malaria. TDR/CHEMaL-SWG (4)/QHS/81.3. Geneva, WHO/TDR
- 16 Klayman D L, Lin A J, Acton N, Scovill J P, Hock J M, Milhous W K. et al . Isolation of artemisinin (qinghaosu) from Artemisia annua growing in the United States. J Nat Prod. 1984; 47 715-7
- 17 Balachandran S, Vishwakarma R A, Popli S P. Chemical investigation of some Artemisia annua species: search for artemisinin or other related sesquiterpene lactones with a peroxide bridge. Ind J Pharm Sci. 1987; 49 152-4
- 18 Acton N, Klayman D L, Rollman I J. Reductive electrochemical HPLC assay for artemisinin (qinghaosu). Planta Med. 1985; 5 445-6
- 19 Ferreira J FS, Simon J E, Janick J. Relationship of artemisinin content of tissue cultured, green house and field grown plants of Artemisia annua . Planta Med. 1995; 61 351-5
- 20 Liersch R, Soicke H, Stehr C, Tullner H U. Formation of artemisinin in Artemisia annua during one vegetation period. Planta Med. 1986; 52 387-90
- 21 Martinez B C, Staba J. The production of artemisinin in Artemisia annua L. tissue cultures. Adv Cell Cult. 1988; 6 69-87
- 22 Charles D J, Cebert E, Simon J E. Characterization of the essential oils of Artemisia annua L. J Ess Oil Res. 1991; 3 33-9
- 23 Duke M V, Paul R N, ElSohly H N, Sturtz G, Duke S O. Localization of artemisinin and artemisitene in foliar tissues of glanded and glandless biotypes of Artemisia annua L. Ind J Plant Sci. 1994; 155 365-72
- 24 Singh A, Vishwakarma R A, Husain A. Evaluation of Artemisia annua strains for higher artemisinin production. Planta Med. 1988; 54 475-6
- 25 Acton N, Klayman D L. Artemisitene, a new sesquiterpene lactone endoperoxide from Artemisia annua . Planta Med. 1985; 5 441-2
- 26 El-Sohyl H N, Croom E M, El Feraly F S, Elsherei M M. A large-scale extraction technique of artemisinin from Artemisia annua . J Nat Prod. 1990; 53 1560-4
- 27 Woerdenbag H J, Pras N, Bos R, Visser J F, Hendriks H, Malingre T M. Analysis of artemisinin and related sesquiterpenoids from Artemisia annua L. by combined gas chromatography/mass spectrometry. Phytochem Anal. 1991; 2 215-9
- 28 Woerdenbag H J, Luers J FJ, Van Uden W, Pras N, Malingre T M, Alfermann A W. Production of the new antimalarial drug in shoot cultures of Artemisia annua L. Plant Cell Tiss Org Cult. 1993; 32 247-57
- 29 Morales M R, Charles D J, Simon J E. Seasonal accumulation of artemisinin in Artemisia annua L. Acta Hort. 1993; 344 416-20
- 30 Pras N, Visser J F, Batterman S, Woerdenbag H J, Malingre T M, Lugt C B. Laboratory selection of Artemisia annua L. for high artemisinin yielding types. Phytochem Anal. 1991; 2 80-3
- 31 Singh A, Kaul V K, Mahajan V P, Singh A, Misra L N, Thakur R S. et al . Introduction of Artemisia annua in India and isolation of artemisinin, a promising antimalarial drug. Ind J Pharmaceut Sci. 1986; 48 137-8
- 32 UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases ( 1986). Report of a meeting of the Scientific Working Group on the chemotherapy of malaria. TDR/CHEMaL/ART/86.3. Geneva, WHO/TDR
- 33 Jung M, ElSohly H N, Mc Chesney J D. Artemisinic acid: a versatile chiral synthon and bioprecursor to natural products. Planta Med. 1990; 56 624
- 34 Roth R J, Acton N. Isolation of artemisinic acid from Artemisia annua . Planta Med. 1987; 53 501-2
- 35 Gulati A, Bharel S, Srivastava P S, Abdin M Z, Jain S K. Experimental studies on artemisinin; a herbal remedy to malaria. Fitoterap. 1996; 67 403-10
- 36 Singh M. Effect of nitrogen, phosphorus and potassium nutrition on herb, oil and artemisinin yield of Artemisia annua under semi-arid tropical condition. J Med Arom Plant Sci. 2000; 22/4A 368-9
- 37 Srivastava N K, Sharma S. Influence of micronutrient imbalance on growth and artemisinin content in Artemisia annua . Ind J Pharmaceut Sci. 1990; 52 225
- 38 Yaseen M, Tajuddin . Effect of Plant growth regulators on yield, oil composition and artemisinin from Artemisia annua under temperate condition. J Med Arom Plant Sci. 1998; 20 1038-41
- 39 Shukla A, Abad Farooqi A H, Shukla Y N, Sharma S. Effect of triacontanol and chlormequat on growth, plant hormones and artemisinin yield in Artemisia annua L. Plant Growth Regul. 1992; 11 165-71
- 40 CIMAP (India) Annual Project Report ( 1988 - 89). Development of Agrotechnologies for Artemisia annua for antimalarial drug, artemisinin.
- 41 Chen F T, Zhang G H. Studies on several physiological factors on artemisinin synthesis in Artemisia annua L. Plant Physiol. 1987; 5 26-30
- 42 Ram M, Gupta M M, Naqvi A A, Kumar S. Effect of planting time on the yield of essential oil and artemisinin in Artemisia annua under subtropical condition. J Ess Oil Res. 1997; 9 193-7
- 43 Weathers P J, Cheethan R D, Follansbee E, Theoharides K. Artemisinin production by transformed roots of Artemisia annua . Biotechnol Lett. 1994; 16 1281-6
- 44 Wallaart T E, Pras N, Quax W J. Seasonal variations of artemisinin and its biosynthetic precursors in plants of Artemisia annua of different geographical origin: proof for the existence of chemotypes. Planta Med. 2000; 61 57-62
- 45 CIMAP (India) Annual Project Report ( 1986 - 87). Development of Agrotechnologies for Artemisia annua for antimalarial drug, artemisinin.
- 46 Wallaart T E, Pras N, Quax W J. Seasonal variations of artemisinin and its biosynthetic precursors in tetraploid Artemisia annua plant compared with the diploid wild type. Planta Med. 1999; 65 723-8
- 47 Mueller M S, Karhagombc I B, Hirt H M, Wemakor E. The potential of Artemisia annua L. as locally produced remedy for malaria in the tropics: agricultural, chemical and clinical aspects. Ethanopharmacology. 2000; 73 487-93
- 48 Lin A J, Klayman D L, Hoch J M, Silverton J V, George C F. Thermal rearrangements and decomposition products of artemisinin (qinghaosu). J Org Chem. 1985; 50 4504-8
- 49 Haynes R K, Vonwiller S C. The development of new peroxidic antimalarials. Chem Aust 1991: 64-7
- 50 Haynes R K, Vonwiller S C. From qinghao, marvelous herb of antiquity, to the antimalarial trioxane qinghaosu and some remarkable new chemistry. Acc Chem Res. 1997; 30 73-9
- 51 El Feraly F S, AlMeshal I A, Alyahya M A, Hifnawy M S. On the possible role of quinghao acid in the biosynthesis of artemisinin. Phytochemistry. 1986; 25 2777-8
- 52 Jung M, ElSohly H N, Croom E M, McPhail A T, Donald R. Practical conversion of artemisinic acid into deoxyartemisinin. J Org Chem. 1986; 51 5417-9
- 53 Roth R J, Acton N. A facile semisynthesis of the antimalarial drug qinghaosu. J Chem Educ. 1991; 68 612
- 54 Roth R J, Acton N. On the conversion of dihydorartemisinic acid into artemisinin. J Org Chem. 1992; 57 3610-4
- 55 Lansbury P T, Nowak D M. An efficient partial synthesis of (+)-artemisinin and (+)-deoxoartemisinin. Tetrahedron Lett. 1992; 33 1029-32
- 56 Akhila A, Thakur R S, Popli S P. Biosynthesis of artemisinin in Artemisia annua . Phytochemistry. 1987; 26 1927-30
- 57 Akhila A, Kumkum R, Thakur R S. Biosynthesis of artemisinic acid in Artemisia annua . Phytochemistry. 1990; 29 2129-32
- 58 Brown G D. Two new compounds from Artemisia annua . J Nat Prod. 1993; 55 1756-60
- 59 Bharel S, Gulati A, Abdin M Z, Srivastava P S, Jain S K. Structure, biosynthesis and function of artemisinin. Fitoterap. 1996; 67 387-402
- 60 Sangwan R S, Agarwal K, Luthra R, Thakur R S, Singh Sangwan N. Biotransformation of artemisinic acid into arteannuin B and artemisinin in Artemisia annua . Phytochemistry. 1993; 34 1301-2
- 61 Wang Y, Xia Z Q, Zhou F Y, Wu Y I, Huang J J, Wang Z Z. Studies on the biosynthesis of arteannuinin III. Arteannuic acid as a key intermediate in biosynthesis of arteannuin and arteannuin B. Acta Chem Sin. 1988; 4 386-7
- 62 Kudakasseril G J, Lam L and Staba E J. Effect of sterol inhibitors on the incorporation of 14C-isopentenyl pyrophosphate into artemisinin by a cell-free system from Artemisia annua tissue cultures and plants. Planta Med. 1987; 53 280-4
- 63 Nair M SR, Basile D V. Bioconversion of arteannuin B to artemisinin. J Nat Prod. 1993; 56 1559-66
- 64 Kim N C, Kim S U. Biosynthesis of artemisinin from 11,12-dihydroarteannuic acid. J Kor Agric Chem Soc Rev. 1992; 35 106-9
- 65 Wallaart T E, Uden W V, Lubberink H GM, Woerdenbag H J, Pras N, Quax W J. Isolation and identification of dihydroartemisinic acid from Artemisia annua and its possible role in the biosynthesis of artemisinin. J Nat Prod. 1999; 62 430-3
- 66 Wallaart T E, Pras N, Quax W J. Isolation and identification of dihydroartemisinic acid hydroperoxide from Artemisia annua: A novel biosynthetic precursor of artemisinin. J Nat Prod. 1999; 62 1160-2
- 67 Bharel S, Gulati A, Abdin M Z, Srivastava P S, Vishwakarma R A, Jain S K. Enzymatic synthesis of artemisinin from natural and synthetic precursors. J Nat Prod. 1998; 61 633-6
- 68 Wang Y, Xia Z, Zhou F, Wu Y, Huang J, Wang Z Z. Studies on biosynthesis of arteannuin IV. The biosynthesis of arteannuin and arteannuin B by the leaf homogenate of A. annua . Chin J Chem. 1993; 11 452-63
- 69 Abdin M Z, Israr M, Srivastava P S, Jain S K. In vitro production of artemisinin, a novel antimalarial compound from Artemisia annua L. J Med Arom Plant Sci. 2000; 22/4A 378-84
- 70 He X C, Zeng M Y, Li G F, Liang Z. Callus induction and regeneration of plantlets from Artemisia annua and changes in qinghaosu contents. Acta Bot Sin. 1983; 25 87-90
-
71 Simon J E, Charles D, Cebert E, Grant L, Janick J, Whipkey A.
Artemisia annua L, a promising aromatic and medicinal. In: Janick J, Simon JE, editors
Advances in New Crops . West Lafayette; Timber Press 1990: 522-6 - 72 Jha S J, Jha T B, Mahato S B. Tissue culture of Artemisia annua l. A potential source of an antimalarial drug. Curr Sci. 1988; 57 344-6
- 73 Whipkey A, Simon J E, Charles D J, Janick J. In vitro production of artemisinin from Artemisia annua L. Phytother Res. 1992; 1 15-25
- 74 Tawfiq N K, Anderzon L A, Roberts M F, Phillipson J D, Bray D H, Warhurst D C. Antiplasmodial activity of Artemisia annua plant cell culture. Plant Cell Rep. 1989; 8 425-8
- 75 Gulati A, Bharel S, Jain S K, Abdin M Z, Srivastava P S. In vitro micropropagation and flowering in Artemisia annua . J Plant Biochem Biotech. 1996; 5 31-5
- 76 El hag H M, ElDomiaty M M, El Feraly F S, Mossa J S, ElOlemy M M. Selection and micropropagation of high artemisinin producing clones of Artemisia annua L. Phytother Res. 1992; 6 20-4
- 77 Fulzele D P, Sipahimalani A T, Heble M R. Tissue cultures of Artemisia annua: organogenesis and artemisinin production. Phytother Res. 1991; 5 149-53
- 78 Woerdenbag H J, Luers J FJ, van Uden W, Pras N, Malingre T M, Alfermann A W. Production of the new antimalarial drug artemisinin in shoot cultures of Artemisia annua . Plant Cell Tissue Org Cult. 1993; 32 247-57
- 79 Paniego N B, Giuletti A M. Artemisia annua L. Dedifferentiated and differentiated cultures. Plant Cell Tissue Org Cult. 1994; 36 163-8
- 80 Kumar V R, Narasu M L, Kishor P BK. Factors affecting in vitro production of artemisinin. Plant tissue culture and biotechnology: emerging trends. Proceedings of a symposium held at Hyderabad, India 29 - 31 January 1997: 249-60
- 81 Kumar V R. In vitro studies on artemisinin production from Artemisia annua Ph. D. Thesis. Jawaharlal Nehru Technological University Hyderabad, India; 1997
- 82 Ferreira J F, Janick J. Immunoquantitative analysis of artemisinin from A. annua using polyclonal antibodies. Phytochemistry. 1996; 41 97-104
- 83 Fulzele D P, Heble M R, Rao P S. Production of terpenoid from Artemisia annua L. plantlet cultures in bioreactor. J Biotechnol. 1995; 40 139-43
- 84 Charles D J, Simon J E, Wood K V, Heinsten P. Germplasm variation in artemisinin content of Artemisia annua using an alternative method of artemisinin analysis from crude plant extracts. J Nat Prod. 1990; 53 157-60
- 85 Smith T C, Weathers P S, Cheetan R D. Effect of gibberillic acid on hairy root cultures of Artemisia annua growth and artemisinin production. In vitro Cell Dev Biol Plant. 1997; 33 75-9
- 86 Delabays N, Benakis A, Collet G. Selection and breeding for high artemisinin (Qinghaosu) yielding strain of Artemisia annua . Acta Hort. 1993; 330 203-7
- 87 Jaziri M, Shimonura k, Yoshimatsu K, Fauconnier M L, Marlier M, Homes J. Establishment of normal and transformed root cultures of Artemisia annua L. for artemisinin production. J Plant Physiol. 1995; 145 175-7
- 88 Paniego N B, Giuletti A M. Artemisinin production by Artemisia annua L. transformed organ cultures. Enzyme Microb Tech. 1996; 18 526-30
- 89 Qin M B, Lig G Z, Yun Y, Ye H C, Li G F. Induction of hairy root from Artemisia annua with Agrobacterium rhizogenes and its culture in vitro . Acta Bot Sin. 1994; 36 (Suppl) 165-70
- 90 Vergauwe A, Cammaert R, Vandenberghe D, Genetello C, Van Montagu M, Vanden Eeckhout E. Agrobacterium tumefaciens-mediated transformation of Artemisia annua L. and regeneration of transgenic plant. Plant Cell Rep. 1996; 15 929-37
- 91 Ghosh B, Mukherjee S, Jha S. Genetic transformation of Artemisia annua by Agrobacterium tumefaciens and artemisinin synthesis in transformed cultures. Plant Sci. 1997; 122 193-9
- 92 Chen- D aHua, Meng Y, Ye H C, Li G F, Chen X Y, Chen D H,. et al . Cultures of transgenic Artemisia annua hairy root with cadinene synthase gene. Acta Bot Sin. 1998; 40 711-4
- 93 Liu B, Ye H, Li G, Chen D, Geng S, Zhang Y. et al . Studies on dynamics of growth and biosynthesis of artemisinin in hairy roots of Artemisia annua L. Chin J Biotehchnol. 1998; 14 248-54
- 94 Chen D, Ye H, Li G. Expression of a chimeric farnesyl diphosphate synthase gene in Artemisia annua L. transgenic plants via Agrobacterium tumefaciens-mediated transformation. Plant Sci. 2000; 155 179-85
- 95 Sa G, Mi M, He-chun Y, Ben-ye L, Guo-feng L, Kang C. Effect of ipt gene expression on the physiological and chemical characteristics of Artemisia annua L. Plant Sci. 2001; 160 691-8
Dr. M. Z. Abdin
Centre for Biotechnology
Faculty of Science
Hamdard University,
New Delhi - 110 062
India
Email: mzabdin@rediffmail.com
Fax: +91-11-60888874