The Molecular Cloning of Dihydroartemisinic Aldehyde Reductase and its Implication in Artemisinin Biosynthesis in Artemisia annua
Open accessAbstract
A key point in the biosynthesis of the antimalarial drug artemisinin is the formation of dihydroartemisinic aldehyde which represents the key difference between chemotype specific pathways. This key intermediate is the substrate for several competing enzymes, some of which increase the metabolic flux towards artemisinin, and some of which--as we show in the present study--may have a negative impact on artemisinin production. In an effort to understand the biosynthetic network of artemisinin biosynthesis, extracts of A. annua flowers were investigated and found to contain an enzyme activity competing in a negative sense with artemisinin biosynthesis. The enzyme Red1 is a broad substrate oxidoreductase belonging to the short chain dehydrogenase/reductase family with high affinity for dihydroartemisinic aldehyde and valuable monoterpenoids. Spatial and temporal analysis of cDNA revealed Red1 to be trichome specific. The relevance of Red1 to artemisinin biosynthesis is discussed.
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Xu, Z., Li, C., Wang, X., Lv, Z., Li, W., & Chen, W. (2025) · Physiologia Plantarum · doi:10.1111/ppl.70207 · Cited by 1 · see citing works
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Nguyen, K. V. (2011) · Digital WPI
Xu, Z., Li, C., Wang, X., et al. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4793844
Metabolic Engineering von Artemisia annua L.
Tu, Y. (2024) · Springer eBooks · doi:10.1007/978-3-662-68757-4_8
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Liu, J., Chen, Y., & He, H. (2026) · Bioresource Technology · doi:10.1016/j.biortech.2026.134823
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Shu, G., Su, F., Tang, Y., Li, J., Nagdy, M. M., Zeng, L., Zhang, F., Chen, M., Mao, J., & Liao, Z. (2026) · Horticulture Research · doi:10.1093/hr/uhag287
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Self-citation
- Authors
- Rydén, A.-M., Ruyter-Spira, C., Quax, W., Osada, H., Muranaka, T., Kayser, O., & Bouwmeester, H.
- Affiliations
- University of Groningen (NL)
- Wageningen University & Research (NL)
- RIKEN (JP)
- TU Dortmund University (DE)
- ORCID
- Venue
- Planta Medica
- Publisher
- Georg Thieme Verlag KG
- Published
- 2010-05-19
- Volume
- 76
- Issue
- 15
- Pages
- 1778-1783
- ISSN
- 0032-0943 (ISSN-L)
- 1439-0221
- OpenAlex
- W2138684500
- Cited by
- 61
- References
- 0
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 2 · 2013: 5 · 2012: 5
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- green
- research.wur.nl
- Locations
- Planta Medica (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (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
- artemisinin biosynthesis, Artemisia annua, Red1, short-chain dehydrogenase/reductase family, chemotypes, metabolic flux, antimalarial drugs
- MeSH terms
- Aldehyde Reductase, Amino Acid Sequence, Cloning, Molecular, Gas Chromatography-Mass Spectrometry, Plant Proteins, DNA, Complementary, Expressed Sequence Tags, Sequence Analysis, Protein, Artemisia annua, Flowers, Artemisinins
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