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Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
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MetaCyc Pathway: artemisinin biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis Terpenoids Biosynthesis Sesquiterpenoids Biosynthesis Sesquiterpene Lactone Biosynthesis

Some taxa known to possess this pathway include ? : Artemisia annua

Expected Taxonomic Range: Artemisia

Summary:
General Background

Artemisinin, a sesquiterpene lactone with an endoperoxide bridge belongs to one of the most potent antimalarial drugs [Woerdenbag90, Abdin03]. Every year, malaria affects 300-500 million people worldwide accounting for about 2 million fatal infections caused by the protozoa Plasmodium falciparum that is carried by mosquitoes of the genus Anopheles [White99]. Artemisia annua (sweet wormwood) is the only plant that contains artemisinin in an amount (0.01-0.8% dry weight) that allows commercially exploitation. Artemsinin and derivatives are particularly effective in treatments of multidrug-resistant malaria replacing other drugs of natural sources that have become ineffective [Van97a].

In addition, artemisinin also shows antiviral activity and has been successfully tested as a treatment against hepatitis B virus (HBV) [Romero05]. Dihydroartemisinin has recently been reported to possess angiogenic activity. The advantage of artemisinin and derivatives lies in their proven low toxicity which makes the compounds useful for the chemotherapeutic treatment of human diseases such as chronic myeloid leukemia (CML) [Lee06b].

However, on a global scale the yield of artemsisinin extracted from Artemisia annua cannot accommodate the demand for the relevant people in the third world. Research had been focused on improving the production of the drug in Artemisia annua cell lines or breeding of high artemisinin yielding plants. However, this approach has not been successful and the scientific effort has now shifted towards the elucidation of the pathway to find and genetically engineer the enzymes responsible for the rate-limiting steps in this pathway [Abdin03].

About This Pathway

The growing demand for artemisinin and derivatives and the failure to achieve a better yield through more conservative approaches has led to an intensified research to understand the biosynthetic pathway and the characterization of the involved enzymes. The sesquiterpene lactone artemisinin derives from (2E,6E)-farnesyl diphosphate (FDP), a ubiquitous precursor for the formation of olefinic sesquiterpene skeletons. The biosynthesis of sesquiterpenes starts with the cyclization of FDP catalyzed by sequiterpene synthases, which can lead to a remarkable diversity of more than 300 types of cyclic sesquiterpenes [McCarvey95]. The first committed step in the biosynthetic route towards artemisinin is the cyclization of (2E,6E)-farnesyl diphosphate to form amorpha-4,11-diene. The enzyme catalyzing that reaction (amorpha-4,11-diene synthase) has been isolated, cloned and biochemical characterized from Artemisia annua [Bouwmeester99, Chang00, Wallaart01, Mercke00, Picaud05].

The other steps of the pathway are less well characterized. However, the metabolic sequence leading from amorpha-4,11-diene to artemisinin has been identified based upon the analysis of intermediates and corresponding enzyme activities [Bertea05]. The formation of artemisinic alcohol from amorpha-4,11-diene is catalyzed by a multifunctional Cytochrome P450 dependent monooxygenase [Teoh06] which can further oxidize artemisinic alcohol to artemisinic aldehyde and convert the aldehyde to artemisinate. The possible further conversation from there to artemisinin has not yet reported and remains to be shown. The involvement of (11R)-dihydroartemisinic aldehyde and dihydroartemisinate in the pathway has been demonstrated and the first step, i.e. the formation of (11R)-dihydroartemisinic aldehyde from artemisinic aldehyde has been attributed to the catalytic activity of a dehydrogenase [Bertea05]. The final steps forming artemisinin from dihydroartemisinate are non-enzymatical, most probably photochemical conversions [Wallaart99, Wallaart99a].

Credits:
Created 15-May-2006 by Foerster H , TAIR
Revised 07-May-2014 by Foerster H , Boyce Thompson Institute


References

Abdin03: Abdin MZ, Israr M, Rehman RU, Jain SK (2003). "Artemisinin, a novel antimalarial drug: biochemical and molecular approaches for enhanced production." Planta Med 69(4);289-99. PMID: 12709893

Bertea05: 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(1);40-7. PMID: 15678372

Bouwmeester99: Bouwmeester HJ, Wallaart TE, Janssen MH, van Loo B, Jansen BJ, Posthumus MA, Schmidt CO, De Kraker JW, Konig WA, Franssen MC (1999). "Amorpha-4,11-diene synthase catalyses the first probable step in artemisinin biosynthesis." Phytochemistry 52(5);843-54. PMID: 10626375

Chang00: 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(2);178-84. PMID: 11185551

Lee06b: Lee J, Zhou HJ, Wu XH (2006). "Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells." Cancer Chemother Pharmacol 57(2);213-20. PMID: 16075280

McCarvey95: McCarvey DJ, Croteau R (1995). "Terpenoid Metabolism." The Plant Cell, 7(7), 1015-1026.

Mercke00: 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(2);173-80. PMID: 11032404

Picaud05: Picaud S, Olofsson L, Brodelius M, Brodelius PE (2005). "Expression, purification, and characterization of recombinant amorpha-4,11-diene synthase from Artemisia annua L." Arch Biochem Biophys 436(2);215-26. PMID: 15797234

Romero05: Romero MR, Efferth T, Serrano MA, Castano B, Macias RI, Briz O, Marin JJ (2005). "Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an "in vitro" replicative system." Antiviral Res 68(2);75-83. PMID: 16122816

Teoh06: 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(5);1411-6. PMID: 16458889

Van97a: Van Geldre E, Vergauwe A, Van den Eeckhout E (1997). "State of the art of the production of the antimalarial compound artemisinin in plants." Plant Mol Biol 33(2);199-209. PMID: 9037139

Wallaart01: Wallaart TE, Bouwmeester HJ, Hille J, Poppinga 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(3);460-5. PMID: 11289612

Wallaart99: Wallaart TE, van Uden W, Lubberink HG, Woerdenbag HJ, Pras N, Quax WJ (1999). "Isolation and identification of dihydroartemisinic acid from Artemisia annua and its possible role in the biosynthesis of artemisinin." J Nat Prod 62(3);430-3. PMID: 10096851

Wallaart99a: Wallaart TE, Pras N, Quax WJ (1999). "Isolation and identification of dihydroartemisinic acid hydroperoxide from Artemisia annua: A novel biosynthetic precursor of artemisinin." J Nat Prod 62(8);1160-2. PMID: 10479327

White99: White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, Kokwaro G, Ouma J, Hien TT, Molyneux ME, Taylor TE, Newbold CI, Ruebush TK, Danis M, Greenwood BM, Anderson RM, Olliaro P (1999). "Averting a malaria disaster." Lancet 353(9168);1965-7. PMID: 10371589

Woerdenbag90: Woerdenbag HJ, Lugt CB, Pras N (1990). "Artemisia annua L.: a source of novel antimalarial drugs." Pharm Weekbl Sci 12(5);169-81. PMID: 2255584

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Covello07: Covello PS, Teoh KH, Polichuk DR, Reed DW, Nowak G (2007). "Functional genomics and the biosynthesis of artemisinin." Phytochemistry 68(14);1864-71. PMID: 17399751

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Nov 23, 2014, biocyc14.