Biotransformation of arteannuic acid into arteannuin-B and artemisinin in Artemisia annua

Sangwan, Rajender S.; Agarwal, Krishna; Luthra, Rajesh; Thakur, Raghunath S.; Singh-Sangwan, Neelam

doi:10.1016/0031-9422(91)80019-w

Cited by 67 publications

(47 citation statements)

References 10 publications

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“…After feeding 14C-labelled artemisinic acid to A. annua twigs, radioactivity was observed in both arteannuin B and artemisinin, suggesting that artemisinic acid is a common precursor for these sesquiterpene lactones [22]. Arteannuin B is considered to be an intermediate in the bioconversion of artemisinic acid to artemisinin, because it was converted to artemisinin using crude and semi-purified cell-free extracts of leaf homogenates of A.…”

Section: Phytochemical Aspectsmentioning

confidence: 99%

Progress in the research of artemisinin-related antimalarials: An update

et al. 1994

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Artemisinin, a sesquiterpene lactone endoperoxide isolated from Artemisia annua L., and a number of its semisynthetic derivatives have shown to possess antimalarial properties. They are all effective against Plasmodium parasites that are resistant to the newest and commonly used antimalarial drugs. This article gives a survey of the literature dealing with artemisinin-related antimalarial issues that have appeared from the end of 1989 up to the beginning of 1994. A broad range of medical and pharmaceutical disciplines is covered, including phytochemical aspects like the selection of high-producing plants, analytical procedures, and plant biotechnology. Furthermore, the organic synthesis of artemisinin derivatives is discussed, as well as their mechanism of action and antimalarial activity, metabolism and pharmacokinetics, clinical studies, side-effects and toxicology, and biological activities other than antimalarial activity.

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Section: Phytochemical Aspectsmentioning

confidence: 99%

Progress in the research of artemisinin-related antimalarials: An update

et al. 1994

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“…However, a large enrichment of arteannuin B was observed suggesting this may be the end product in the artemisinic acid pathway and not artemisinin as had been previously hypothesized [48]. Additionally, Brown and Sy saw no conversion to dihydroartemisinic acid which suggested that the chemotypes proposed by Wallaart et al [33] are in fact differences in the balance between these two pathways.…”

Section: Artemisinln Biosynthetic Pathwaymentioning

confidence: 67%

“…This pre-artemisinic acid split is bolstered by the work of Brown and Sy [47] who fed 13 C labeled artemisinic acid to intact plantlets through cut shoots and observed no conversion to artemisinin. However, a large enrichment of arteannuin B was observed suggesting this may be the end product in the artemisinic acid pathway and not artemisinin as had been previously hypothesized [48]. Additionally, Brown and Sy saw no conversion to dihydroartemisinic acid which suggested that the chemotypes proposed by Wallaart et al [33] are in fact differences in the balance between these two pathways.…”

Section: Artemisinln Biosynthetic Pathwaymentioning

confidence: 68%

Recent Advances in Artemisinin Production Through Heterologous Expression

Arsenault

Wobbe²,

Weathers³

2008

CMC

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Artemisinin the sesquiterpene endoperoxide lactone extracted from the herb Artemisia annua, remains the basis for the current preferred treatment against the malaria parasite Plasmodium falciparum. In addition, artemisinin and its derivatives show additional anti-parasite, anti-cancer, and anti-viral properties. Widespread use of this valuable secondary metabolite has been hampered by low production in vivo and high cost of chemical synthesis in vitro. Novel production methods are required to accommodate the ever-growing need for this important drug. Past work has focused on increasing production through traditional breeding approaches, with limited success, and on engineering cultured plants for high production in bioreactors. New research is focusing on heterologous expression systems for this unique biochemical pathway. Recently discovered genes, including a cytochrome P450 and its associated reductase, have been shown to catalyze multiple steps in the biochemical pathway leading to artemisinin. This has the potential to make a semisynthetic approach to production both possible and cost effective. Artemisinin precursor production in engineered Saccharomyces cerevisiae is about two orders of magnitude higher than from fieldgrown A. annua. Efforts to increase flux through engineered pathways are on-going in both E. coli and S. cerevisiae through combinations of engineering precursor pathways and downstream optimization of gene expression. This review will compare older approaches to overproduction of this important drug, and then focus on the results from the newer approaches using heterologous expression systems and how they might meet the demands for treating malaria and other diseases. KeywordsAmorpha diene; CYP71 AV1; terpenoid; genetic engineering; malaria ARTEMISININ: EFFECTIVE AGAINST MALARIA AND OTHER DISEASESIn low income and developing nations, malaria is the fifth most prevalent infectious disease and the tenth overall cause of death and is projected to remain at that level until at least 2030 [1,2]. The UN World Health Organization (WHO) estimates that more than 380 million cases of malaria occur each year and account for more than 1 million deaths. Furthermore, while not always fatal, the malaria burden has been estimated at more than 46 million disease adjusted *Address correspondence to this author at the Worcester Polytechnic Institute, Worcester, MA 01609, USA; Tel: 508-831-5196%; Fax: 508-831-5396%; weathers@wpi.edu. NIH Public Access Author ManuscriptCurr Med Chem. Author manuscript; available in PMC 2010 February 15. Published in final edited form as:Curr Med Chem. 2008 ; 15(27): 2886. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript life years (DALY) [3]. Though virtually eradicated in temperate climates and developed nations, developing nations still suffer a significant malaria burden.Artemisinin and its more potent derivatives (Table 1) all contain an endoperoxide bridge that is required for therapeutic activity and these drugs provide an effective cure o...

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“…Further modifications of amorpha-4,11-diene to produce the next proven intermediate in artemisinin biosynthesis, artemisinic acid (Sangwan et al 1993a), can be envisaged to occur analogously to the formation of the diterpenoids kaurenic and abietic acid from kaurene and abietadiene, respectively, and of the sesquiterpenoid germacrene acid from germacrene A (Funk and Croteau 1994;De Kraker et al 2001;West 1980). The first likely step is the cytochrome-P450-catalysed hydroxylation at C12 of amorpha-4,11-diene yielding artemisinic alcohol.…”

Section: Biosynthetic Pathway Beyond Amorpha-411-dienementioning

confidence: 99%

“…Knowledge of the exact biosynthesis of artemisinin should enable us to influence its formation in a direct way, for example by metabolic engineering. Several authors have demonstrated that A. annua converts artemisinic (also named arteannuic) acid and dihydroartemisinic (also named dihydroarteannuic) acid to artemisinin (Sangwan et al 1993a;Wallaart et al 1999b) (Figure 1). Akhila and coworkers (Akhila et al 1990) hypothesized a pathway in which the formation from FDP of an unidentified enzyme-bound sesquiterpene-like intermediate represents the first committed step in the biosynthesis of artemisinin.…”

Section: Introductionmentioning

confidence: 99%

Research to Improve Artemisinin Production for use in the Preparation of Anti-Malarial Drugs

Bouwmeester

Bertea²,

Kraker³

et al.

Medicinal and Aromatic Plants

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Abstract. An important group of antimalarial drugs consists of the endoperoxide sesquiterpene lactone artemisinin and its semi-synthetically prepared derivatives. Because of the development of resistance against other malarial drugs, the demand for artemisinin has rapidly increased during the past decade. However, the supply of artemisinin is troublesome as neither total nor semi-synthesis are economically feasible and the only plant species known to produce artemisinin, Artemisia annua L., contains only low amounts of this compound. For a directed strategy to improve artemisinin production, one of the first requirements is to have insight into the regulation of its biosynthesis. Surprisingly, until some years ago hardly anything was known about the biosynthesis of artemisinin, particularly about the early enzymatic steps leading to (dihydro)artemisinic acid. To elucidate this important missing part in the pathway, we have analysed the terpenoids in A. annua leaves and the presence of sesquiterpene synthases, the enzyme class that should theoretically catalyse the first step in the formation of artemisinin. This led to the discovery of amorpha-4,11-diene synthase, which indeed catalyses the first step in artemisinin biosynthesis and for which the corresponding gene was cloned shortly afterwards. A subsequent search for oxidized derivatives of amorpha-4,11-diene -which could be postulated to be intermediates en route to artemisinin -revealed the presence of artemisinic alcohol, dihydroartemisinic alcohol, artemisinic aldehyde, dihydroartemisinic aldehyde and dihydroartemisinic acid. We also demonstrated the presence of the biosynthetic enzymes amorpha-4,11-diene hydroxylase, artemisinic alcohol dehydrogenase, artemisinic aldehyde reductase and dihydroartemisinic aldehyde dehydrogenase in A. annua. From these results, we conclude that the early steps in artemisinin biosynthesis involve: cyclization of farnesyl diphosphate by amorpha-4,11-diene synthase to amorpha-4,11-diene, hydroxylation of amorpha-4,11-diene to artemisinic alcohol, oxidation of artemisinic alcohol to artemisinic aldehyde, reduction of the C11-C13 double bond yielding dihydroartemisinic aldehyde, and oxidation of dihydroartemisinic aldehyde to dihydroartemisinic acid. During this biochemical research we have also managed to develop a trichome isolation protocol which has not only accelerated our biochemical work but also enables us to clone -in a very directed way -the genes that encode the enzymes responsible for artemisinin production. This should in the next few years result in several approaches to boost artemisinin production. 276H. BOUWMEESTER ET AL.

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Biotransformation of arteannuic acid into arteannuin-B and artemisinin in Artemisia annua

Cited by 67 publications

References 10 publications

Progress in the research of artemisinin-related antimalarials: An update

Progress in the research of artemisinin-related antimalarials: An update

Recent Advances in Artemisinin Production Through Heterologous Expression

Research to Improve Artemisinin Production for use in the Preparation of Anti-Malarial Drugs

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