Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways
Abstract
The potent antimalarial sesquiterpene lactone, artemisinin, is produced in low quantities by the plant Artemisia annua L. The source and regulation of the isopentenyl diphosphate (IPP) used in the biosynthesis of artemisinin has not been completely characterized. Terpenoid biosynthesis occurs in plants via two IPP-generating pathways: the mevalonate pathway in the cytosol, and the non-mevalonate pathway in plastids. Using inhibitors specific to each pathway, it is possible to resolve which supplies the IPP precursor to the end product. Here, we show the effects of inhibition on the two pathways leading to IPP for artemisinin production in plants. We grew young (7-14 days post cotyledon) plants in liquid culture, and added mevinolin to the medium to inhibit the mevalonate pathway, or fosmidomycin to inhibit the non-mevalonate pathway. Artemisinin levels were measured after 7-14 days incubation, and production was significantly reduced by each inhibitor compared to controls, thus, it appears that IPP from both pathways is used in artemisinin production. Also when grown in miconazole, an inhibitor of sterol biosynthesis, there was a significant increase in artemisinin compared to controls suggesting that carbon was shifted from sterols into sesquiterpenes. Collectively these results indicate that artemisinin is probably biosynthesized from IPP pools from both the plastid and the cytosol, and that carbon from competing pathways can be channeled toward sesquiterpenes. This information will help advance our understanding of the regulation of in planta production of artemisinin.
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Treating A. annua plants with fosmidomycin at 100 μM for 14 days decreased artemisinin content by 25% compared to controls.
“Treating A. annua plants with fosmidomycin at 100 µM for 14 days decreased artemisinin content by 25% compared to controls (Towler and Weathers 2007).”
From Enhancing artemisinin content in and delivery from Artemisia annua: a review of alternative, classical, and transgenic approaches (2021) · cites this paper as Towler and Weathers 2007
A large number of other cadinane and amorphane sesquiterpenes have been suggested as late-stage intermediates at or around the juncture between phases 2 and 3 of artemisinin biosynthesis.
“A large number of other cadinane and amorphane sesquiterpenes, including: arteannuin B (462) [248,285]; epi-deoxyarteannuin B (478) [286]; dihydroarteannuin B (479) [249]; dihydro-epi-deoxyarteannuin B (485) [286]; the seco-cadinane (494) [217]; and artemisitene (497) [211,248,284] have also been suggested as late-stage intermediates at or around this point in the biosynthesis”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [286]
Dihydroartemisinic acid (480), rather than artemisinic acid (473), is the true late-stage precursor to artemisinin (495).
“it is consistent with much of the more recent literature (post-1990’s), in which there is now a gathering consensus that dihydroartemisinic acid (480), rather than artemisinic acid (473), is the true late-stage precursor to artemisinin (495).”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [286]
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Self-citation
- Authors
- Towler, M. J., & Weathers, P. J.
- Affiliations
- Worcester Polytechnic Institute (US)
- Corresponding author
- Weathers, Pamela J.
- ORCID
- Weathers, Pamela J.
- Venue
- Plant Cell Reports
- Published
- 2007-08-21
- Volume
- 26
- Issue
- 12
- Pages
- 2129-2136
- ISSN
- 0721-7714 (ISSN-L)
- 1432-203X
- OpenAlex
- W2057823601
- Cited by
- 170
- References
- 39
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 13 · 2023: 6 · 2022: 5 · 2021: 9 · 2020: 3 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 12 · 2015: 8 · 2014: 9 · 2013: 16 · 2012: 13
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Plant Cell Reports (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Arkansas Biosciences Institute
- National Institutes of Health
- National Institute of General Medical Sciences (R15GM069562)
- 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
- artemisinin biosynthesis, isopentenyl pyrophosphate, mevalonate pathway, methylerythritol phosphate pathway, Artemisia annua, sesquiterpene lactones, lovastatin, fosmidomycin, miconazole, sterol biosynthesis, carbon allocation, antimalarial compounds
- MeSH terms
- Antimalarials, Carbon, Cytosol, Lovastatin, Mevalonic Acid, Miconazole, Models, Biological, Organophosphorus Compounds, Plastids, Biomass, Cotyledon, Artemisia annua, Artemisinins, Hemiterpenes
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