The Molecular Cloning of Artemisinic Aldehyde Δ11(13) Reductase and Its Role in Glandular Trichome-dependent Biosynthesis of Artemisinin in Artemisia annua
Open accessAbstract
At some point during biosynthesis of the antimalarial artemisinin in glandular trichomes of Artemisia annua, the Delta11(13) double bond originating in amorpha-4,11-diene is reduced. This is thought to occur in artemisinic aldehyde, but other intermediates have been suggested. In an effort to understand double bond reduction in artemisinin biosynthesis, extracts of A. annua flower buds were investigated and found to contain artemisinic aldehyde Delta11(13) double bond reductase activity. Through a combination of partial protein purification, mass spectrometry, and expressed sequence tag analysis, a cDNA clone corresponding to the enzyme was isolated. The corresponding gene Dbr2, encoding a member of the enoate reductase family with similarity to plant 12-oxophytodienoate reductases, was found to be highly expressed in glandular trichomes. Recombinant Dbr2 was subsequently characterized and shown to be relatively specific for artemisinic aldehyde and to have some activity on small alpha,beta-unsaturated carbonyl compounds. Expression in yeast of Dbr2 and genes encoding four other enzymes in the artemisinin pathway resulted in the accumulation of dihydroartemsinic acid. The relevance of Dbr2 to trichome-specific artemisinin biosynthesis is discussed.
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The enzymatic steps involved in production of the non-phytotoxic precursors amorpha-4,11-diene (A-4,11-D) and dihydroartemisinic acid (DHAA) have been elucidated.
“Although the enzymatic steps involved in production of the non-phytotoxic precursors amorpha-4,11-diene (A-4,11-D) and dihydroartemisinic acid (DHAA) have been elucidated (12-15)”
From <i>Artemisia annua</i> mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [14]
The pathway overview (page not provided) identifies amorpha-4,11-diene synthase and describes biochemical evidence for a route to dihydroartemisinic acid. The Discussion and yeast-production passage further support Dbr2’s role, but the paper says the pathway beyond artemisinic alcohol is less well established. The cited passages also do not establish that either precursor is non-phytotoxic. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDihydroartemisinic acid is formed from artemisinic aldehyde in two steps via dihydroartemisinic aldehyde, catalyzed by DBR2 and ALDH1.
“Dihydroartemisinic acid is formed from artemisinic aldehyde in two steps via dihydroartemisinic aldehyde. The reduction is catalyzed by artemisinic aldehyde Δ11(13) reductase (DBR2) [15] and the oxidation to the acid by aldehyde dehydrogenase 1 (ALDH1) [16].”
From Relative expression of genes of terpene metabolism in different tissues of Artemisia annuaL (2011) · cites this paper as [15]
Artemisinic acid is not converted to dihydroartemisinic acid in A. annua.
“Kim and Kim have reported that artemisinic acid is not converted to dihydroartemisinic acid in A. annua [297]”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [297]
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References 31 · Cited by 312
Research works printed but not linked: 1
- Breithaupt, C., Kurzbauer, R., Lilie, H., Schaller, A., Strassner, J., Huber, R., Macheroux, P., and Clausen, T. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 14337-14342
- Authors
- Zhang, Y., Teoh, K. H., Reed, D. W., Maes, L., Goossens, A., Olson, D. J. H., Ross, A. R. S., & Covello, P. S.
- Affiliations
- Plant Biotechnology Institute (CA)
- Vlaams Instituut voor Biotechnologie (BE)
- Corresponding author
- Covello, Patrick S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 283
- Issue
- 31
- Pages
- 21501-21508
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2129447528
- Cited by
- 312
- References
- 31
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 12 · 2023: 15 · 2022: 12 · 2021: 15 · 2020: 12 · 2019: 15 · 2018: 15 · 2017: 17 · 2016: 27 · 2015: 15 · 2014: 20 · 2013: 24 · 2012: 23
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Universiteit Gent
- Vlaamse Interuniversitaire Raad
- 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, glandular trichomes, double bond reduction, cDNA cloning, yeast expression system, antimalarial compounds
- MeSH terms
- Carbon, Cloning, Molecular, Genetic Vectors, Gas Chromatography-Mass Spectrometry, Models, Chemical, Oxidoreductases, Phylogeny, Plant Proteins, Seeds, Stereoisomerism, Subcellular Fractions, Time Factors, Plant Roots, Artemisia annua, Artemisinins
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