Cyclization mechanism of amorpha-4,11-diene synthase, a key enzyme in artemisinin biosynthesis
Abstract
Cyclization of farnesyl diphosphate into amorpha-4,11-diene by amorpha-4,11-diene synthase (ADS) initiates biosynthesis of artemisinin, a clinically important antimalarial drug precursor. Three possible ring-closure mechanisms, two involving a bisabolyl carbocation intermediate followed by either a 1,3-hydride shift or two successive 1,2-shifts, and one involving a germacrenyl carbocation, were proposed and tested by analyzing the fate of farnesyl diphosphate H-1 hydrogen atoms through (1)H and (2)H NMR spectroscopy. Migration of one deuterium atom of [1,1-(2)H(2)]farnesyl diphosphate to H-10 of amorpha-4,11-diene singled out the bisabolyl carbocation mechanism with a 1,3-hydride shift. Further confirmation was obtained through enzyme reactions with (1R)- and (1S)-[1-(2)H]farnesyl diphosphate. Results showed that deuterium of the 1R compound remained at H-6, whereas that of the 1S compound migrated to H-10 of amorpha-4,11-diene. Incorporation of one deuterium into amorphadiene in the cyclization process was observed when the reaction was performed in (2)H(2)O, as evidenced by an increase of 1 amu in the mass of the molecular ion.
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cDNAs encoding ADS from A. annua have been isolated, sequenced, and expressed.
“cDNAs encoding ADS from A. annua have been isolated, sequenced, and expressed [293,294].”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [294]
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The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao)
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- Authors
- Kim, S.-H., Heo, K., Chang, Y.-J., Park, S.-H., Rhee, S.-K., & Kim, S.-U.
- Affiliations
- Mokpo National University (KR)
- Venue
- Journal of Natural Products
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-01-31
- Volume
- 69
- Issue
- 5
- Pages
- 758-762
- ISSN
- 0163-3864 (ISSN-L)
- 1520-6025
- OpenAlex
- W2068460381
- Cited by
- 78
- References
- 14
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 10 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 9 · 2016: 8 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Natural Products (publishedVersion)
- PubMed (publishedVersion)
- 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
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Keywords
- amorpha-4,11-diene synthase, artemisinin biosynthesis, ring closure mechanism, 1,3-hydride shift, deuterium labeling, stereochemistry
- MeSH terms
- Cyclization, Deuterium, Plants, Medicinal, Polyisoprenyl Phosphates, Sesquiterpenes, Stereoisomerism, Molecular Structure, Artemisia, Alkyl and Aryl Transferases, Nuclear Magnetic Resonance, Biomolecular, Artemisinins
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