Seasonal Variation of Artemisinin and its Biosynthetic Precursors in Plants of Artemisia annua of Different Geographical Origin: Proof for the Existence of Chemotypes

Wallaart, T. Eelco; Pras*, Niesko; Beekman, and, Aäron C.; Quax, Wim J.

doi:10.1055/s-2000-11115

Cited by 283Plant biochemistry and biosynthesisSesquiterpenes and Asteraceae StudiesPlant tissue culture and regeneration

Seasonal Variation of Artemisinin and its Biosynthetic Precursors in Plants of Artemisia annua of Different Geographical Origin: Proof for the Existence of Chemotypes

Wallaart, T. Eelco, Pras*, Niesko, Beekman, and, Aäron C., Quax, Wim J.·2000·Planta Medica

DOI 10.1055/s-2000-11115

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Abstract

The time course of the levels of artemisinin, its biosynthetic precursors and the biosynthetically related sesquiterpenes was monitored during a vegetation period of Artemisia annua plants of different geographical origin. Considerable differences in contents of artemisinin and its direct precursors artemisinic acid and dihydroartemisinic acid were found between these A. annua's. For the first time the A. annua plants of different geographical origin were found to belong to different chemotypes. A chemotype with a high artemisinin level was found to have also a high dihydroartemisinic acid level but a relatively low artemisinic acid level. Reversibly, a chemotype with low levels of artemisinin and dihydroartemisinic acid contained a high artemisinic acid level. Artemisinic acid is considered to be the direct precursor of dihydroartemisinic acid in the biosynthetic pathway of artemisinin. The observed accumulation of artemisinic acid in one of the A. annua chemotypes may indicate the presence of a rate-limiting step in the biosynthetic pathway of artemisinin. The enzymatic reduction of artemisinic acid into dihydroartemisinic acid is probably a "bottle neck" in the biosynthetic pathway of artemisinin in varieties with high artemisinic acid and consequentially low artemisinin levels. After a night-frost period, the level of artemisinin was increased, in the Vietnamese A. annua plants, while the dihydroartemisinic acid level was decreased. This phenomenon is in accordance with our hypothesis that stress triggers the conversion of dihydroartemisinic acid to artemisinin. It is suggested that the presence of high levels of dihydroartemisinic acid may be an adaptation to stress conditions (e.g., night-frost), during which relatively high levels of 1O2 are formed. Dihydroartemisinic acid gives the plant protection by reacting with these reactive oxygen species yielding artemisinin as stable end-product.

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The genetic variation within A. annua appears high; at least two chemotypes with different essential oil compositions have been described.
“The genetic variation within A. annua appears to be high. At least two chemotypes with different compositions of the essential oil during the vegetative period have been described [19].”
From Relative expression of genes of terpene metabolism in different tissues of Artemisia annuaL (2011) · cites this paper as [19]

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“Therefore an alternative explanation for increased biosynthesis of this particular secondary metabolite in response to glucose may be that AN and AB are formed as DHAA and AA, respectively, and act as sinks for reactive oxygen species (ROS), specifically singlet oxygen [33].”
Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis
Zhu, X., Yang, L., Li, Y. J., Zhang, D., Chen, Y., Kostecká, P., Kmonı́èková, E., & Zídek, Z. (2013) · Pharmacological Reports · doi:10.1016/s1734-1140(13)71016-8 · Cited by 55 · see citing works
“Included in the study were sesquiterpene lactone artemisinin and its biogenetic precursors arteannuin B and artemisinic acid [7, 9, 43].”
Background
Variations in key artemisinic and other metabolites throughout plant development in Artemisia annua L. for potential therapeutic use
Towler, M. J., & Weathers, P. J. (2015) · Industrial Crops and Products · doi:10.1016/j.indcrop.2015.01.007 · Cited by 51 · see citing works
“annua has two main chemotypes with one producing mainly artemisinin and the other producing mainly artemisinic acid, so such discrepancies are reasonable (Wallaart et al. 2000; Wu et al. 2011).”
Background
Synthetic chemistry fuels interdisciplinary approaches to the production of artemisinin
Corsello, M. A., & Garg, N. K. (2014) · Natural Product Reports · doi:10.1039/c4np00113c · Cited by 53 · see citing works
Updates on artemisinin: an insight to mode of actions and strategies for enhanced global production
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Bioactive metabolites of plants and microbes and their role in agricultural sustainability and mitigation of plant stress
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A rapid method for the determination of artemisinin and its biosynthetic precursors in Artemisia annua L. crude extracts
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Enhanced artemisinin yield by expression of rol genes in Artemisia annua.
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“Other enzymes like amorphadiene synthase (ADS), cytochrome P450, CYP71AV1 (CYP), double bond reductase 2 (DBR2) and aldehyde dehydrogenase 1 (ALDH1) catalyze different steps of artemisinin biosynthesis [7–11].”
Background
Detailed Phytochemical Analysis of High- and Low Artemisinin-Producing Chemotypes of Artemisia annua
Czechowski, T., Larson, T. R., Catania, T. M., Harvey, D., Wei, C., Essome, M., Brown, G. D., & Graham, I. A. (2018) · Frontiers in Plant Science · doi:10.3389/fpls.2018.00641 · Cited by 47 · see citing works
“annua varieties of European andNorth American origin whichmostly represent the LAP chemotype and the majority of East-Asian origin varieties which represent the HAP chemotype (Wallaart et al., 2000), Details of the genetic divergence of these varieties remains a topic for further investigation that could reveal furthe…”
BackgroundInfluential
Variation in antibacterial and anti-inflammatory activity of different growth forms of Malva parviflora and evidence for synergism of the anti-inflammatory compounds
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“The highest levels of dihydroartemisinic acid and artemisinin were measured in Artemisia annua plants of Vietnamese origin, while the lowest levels of these two compounds were found among the Chinese, European and New world plants (Wallaart et al., 2000).”
Background
Metabolic engineering of chloroplasts for artemisinic acid biosynthesis and impact on plant growth
Saxena, B., Subramani, M., Malhotra, K., Bhavesh, N. S., Potlakayala, S. D., & Kumar, S. B. (2014) · Journal of Biosciences · doi:10.1007/s12038-013-9402-z · Cited by 46 · see citing works
Salicylic acid restrains arsenic induced oxidative burst in two varieties of Artemisia annua L. by modulating antioxidant defence system and artemisinin production
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Medicinal Plant Biotechnology
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Review and future prospects on the mechanisms related to cold stress resistance and tolerance in medicinal plants
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A simple and efficient procedure to enhance artemisinin content in Artemisia annua L. by seeding to salinity stress
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Pilot Plant PAT Approach for the Diastereoselective Diimide Reduction of Artemisinic Acid
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Seasonal variations of natural products in European herbs
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“Denmark Plantaginaceae Antirrhinum majus L. Iridoids Aerial parts Drøhse Høgedal and Mølgaard (2000) The Netherlands Asteraceae Artemisia annua L.3 Artemisinin Leaves Wallaart et al. (2000) Denmark Brassicaceae Barbarea vulgaris R.Br. Glucosinolates Leaves Agerbirk et al. (2001) Serbia Lamiaceae Clinopodium pulegium (…”
Background
Morphological and molecular characterization of selected Artemisia species from Rawalakot, Azad Jammu and Kashmir
Nazar, N., & Mahmood, T. (2010) · Acta Physiologiae Plantarum · doi:10.1007/s11738-010-0545-3 · Cited by 42 · see citing works
“Considerable differences in contents of artemisinin and its precursors were observed (Wallaart et al. 2000).”
Background
Selection and authentication of botanical materials for the development of analytical methods
Applequist, W. L., & Miller, J. S. (2013) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-012-6595-1 · Cited by 41 · see citing works
“Other potential environmental effects include climate or altitude [64, 65], recent weather [50], exposure to herbivores or pathogens that may trigger production of defensive compounds [66–70], perhaps only at certain developmental stages [71], or even such factors as soil type or time of day, depending on the sensitiv…”
Background
Senescent Leaves ofArtemisia annuaare One of the Most Active Organs for Overexpression of Artemisinin Biosynthesis Responsible Genes upon Burst of Singlet Oxygen
Yang, R.-Y., Zeng, X.-M., Lu, Y.-Y., Lu, W.-J., Feng, L.-L., Yang, X.-Q., & Zeng, Q.-P. (2010) · Planta Medica · doi:10.1055/s-0029-1240620 · Cited by 40 · see citing works
Oligomers of carrageenan regulate functional activities and artemisinin production in Artemisia annua L. exposed to arsenic stress
Naeem, M., Nabi, A., Aftab, T., & Khan, M. M. A. (2019) · PROTOPLASMA · doi:10.1007/s00709-019-01475-y · Cited by 40 · see citing works
Synergistic re-channeling of mevalonate pathway for enhanced artemisinin production in transgenic Artemisia annua
Feng, L.-L., Yang, R.-Y., Yang, X.-Q., Zeng, X.-M., Lu, W.-J., & Zeng, Q.-P. (2009) · Plant Science · doi:10.1016/j.plantsci.2009.03.014 · Cited by 39 · see citing works
Molecular Characterization of the 1-Deoxy-D-Xylulose 5-Phosphate Synthase Gene Family in Artemisia annua
Zhang, F., Liu, W., Xia, J., Zeng, J., Xiang, L., Zhu, S., Zheng, Q., Xie, H., Yang, C., Chen, M., et al. (2018) · Frontiers in Plant Science · doi:10.3389/fpls.2018.00952 · Cited by 36 · see citing works
Cumulative role of irradiated sodium alginate and nitrogen fertilizer on growth, biochemical processes and artemisinin production in Artemisia annua
Aftab, T., Naeem, M., Idrees, M., Khan, M. M. A., Moinuddin, & Varshney, L. (2013) · Industrial Crops and Products · doi:10.1016/j.indcrop.2013.08.026 · Cited by 35 · see citing works
Effect of irradiated sodium alginate and phosphorus on biomass and artemisinin production in Artemisia annua
Aftab, T., Khan, M. M. A., Naeem, M., Idrees, M., Siddiqi, T. O., Moinuddin, M., & Varshney, L. (2014) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2014.04.045 · Cited by 35 · see citing works
Cloning of artemisinin biosynthetic cDNAs and novel ESTs and quantification of low temperature-induced gene overexpression
Zeng, Q.-P., Chang, Z., Yin, L., Yang, R., Zeng, X.-M., Huang, Y., Feng, L.-L., & Yang, X. (2008) · Science in China Series C Life Sciences · doi:10.1007/s11427-008-0032-x · Cited by 34 · see citing works
Artemisia annua extract prevents ovariectomy-induced bone loss by blocking receptor activator of nuclear factor kappa-B ligand-induced differentiation of osteoclasts
Lee, S., Kim, H., Park, J., Kim, H., Kim, K., Son, S. H., Park, K.-K., & Chung, W. (2017) · Scientific Reports · doi:10.1038/s41598-017-17427-6 · Cited by 34 · see citing works
Variation in terpenoids in leaves of Artemisia annua grown under different LED spectra resulting in diverse antimalarial activities against Plasmodium falciparum
Sankhuan, D., Niramolyanun, G., Kangwanrangsan, N., Nakano, M., & Supaibulwatana, K. (2022) · BMC Plant Biology · doi:10.1186/s12870-022-03528-6 · Cited by 34 · see citing works
Earlier Flowering Induced by Over‐Expression of CO Gene Does Not Accompany Increase of Artemisinin Biosynthesis in Artemisia annua
Wang, H., Liu, Y., Chong, K., et al. (2007) · Plant Biology · doi:10.1055/s-2006-924634 · Cited by 33 · see citing works
The Influence of Biotic and Abiotic Factors on the Production of Secondary Metabolites in Medicinal Plants
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Artemisia annua Stems a New Sustainable Source for Cellulosic Materials: Production and Characterization of Cellulose Microfibers and Nanocrystals
Risite, H., Salim, M. H., Oudinot, B. T., et al. (2022) · Waste and Biomass Valorization · doi:10.1007/s12649-021-01658-w · Cited by 32 · see citing works
“1 3 has long been grown and used in herbal medicine as early as 168 BC, particularly in ancient China [22], and also it has been used as a source of anti-malarial drugs [23, 24].”
Background
Phenological Variation of the Essential Oil ofArtemisia scopariaWaldst. et Kit from Iran
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Characterization of development and artemisinin biosynthesis in self-pollinated Artemisia annua plants
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Transcriptomic analyses show that 24-epibrassinolide (EBR) promotes cold tolerance in cotton seedlings
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“Under cold stress, the levels of sesquiterpenes in Artemisia annua [54], anthocyanins in Nicotiana tabacum [55], quercetin in Arnica montana L [56], and phloroglucinols in Hypericum spp.”
Background
Distribution and ecological impact of artemisinin derived from Artemisia annua L. in an agricultural ecosystem
Herrmann, S., Jessing, K. K., Jørgensen, N. O. G., Nina Cedergreen, G., Kandeler, E., & Strobel, B. W. (2012) · Soil Biology and Biochemistry · doi:10.1016/j.soilbio.2012.08.011 · Cited by 29 · see citing works

Is Artemisinin the Only Antiplasmodial Compound in the Artemisia annua Tea Infusion? An in Vitro Study
Mouton, J., Jansen, O., Frédérich, M., & van der Kooy, F. (2013) · Planta Medica · doi:10.1055/s-0032-1328324 · Cited by 20 · see citing works
Artemisia annua glandular secretory trichomes： the biofactory of antimalarial agent artemisinin
Ling, Xiao, X., Hexin, et al. (2016) · 中国科学通报：英文版
A review of various efforts to increase artemisinin and other antimalarial compounds in Artemisia Annua L plant
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Self-immobilized aggreage culture of Artemisia annua L. for imroved artemisinin
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Metabolic engineering of artemisinin biosynthesis in Artemisia annua L.
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Authors: Wallaart, T. E., Pras*, N., Beekman, A., & Quax, W. J.
Affiliations: University of Groningen (NL)
ORCID: Quax, Wim J.
Venue: Planta Medica
Publisher: Georg Thieme Verlag KG
Published: 2000-02
Volume: 66
Issue: 1
Pages: 57-62
ISSN: 0032-0943 (ISSN-L)
1439-0221
DOI: 10.1055/s-2000-11115
OpenAlex: W2104781222
Cited by: 281
References: 0
Citations by year: 2026: 5 · 2025: 4 · 2024: 10 · 2023: 7 · 2022: 12 · 2021: 5 · 2020: 10 · 2019: 20 · 2018: 55 · 2017: 9 · 2016: 8 · 2015: 16 · 2014: 15 · 2013: 12 · 2012: 14
FWCI: 0.84
Type: journal article
Language: en
Open access: closed
Locations: Planta Medica (publishedVersion)
PubMed (publishedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant tissue culture and regeneration
Keywords: Artemisia annua, artemisinin, chemotypes, artemisinic acid, dihydroartemisinic acid, sesquiterpenes, biosynthetic precursors, seasonal variation, geographical origin, night frost, reactive oxygen species, stress adaptation, rate-determining step, plant secondary metabolites
MeSH terms: Chromatography, High Pressure Liquid, Gas Chromatography-Mass Spectrometry, Plants, Medicinal, Seasons, Sesquiterpenes, Mass Spectrometry, Artemisia, Artemisinins

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Seasonal Variation of Artemisinin and its Biosynthetic Precursors in Plants of Artemisia annua of Different Geographical Origin: Proof for the Existence of Chemotypes

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