Amorpha-4,11-diene synthase: Mechanism and stereochemistry of the enzymatic cyclization of farnesyl diphosphate
Abstract
Recombinant amorpha-4,11-diene synthase from Artemisia annua, expressed in Escherichia coli, was incubated with the deuterium-labeled farnesyl diphosphates, (1R)-[1-(2)H]FPP, (1S)-[1-(2)H]FPP, and [1,1-(2)H2]FPP. GC-MS analysis of amorpha-4,11-diene formed from the deuterated FPPs shows that the deuterium atoms are retained in the product. Furthermore, analysis of the MS-spectra obtained with the differently labeled substrate indicates that the H-1si-proton of FPP is transferred during the cyclization reaction to carbon 10 of amorphadiene while the H-1re-proton of FPP is retained on C-6 of the product. Proton NMR and COSY experiments proved that the original H-1si-proton of FPP is located at C-10 of amorpha-4,11-diene as a result of a 1,3-hydride shift following initial 1,6-ring closure. The results obtained support the previously suggested mechanism for the cyclization of farnesyl diphosphate by amorph-4,11-diene synthase involving isomerization of FPP to (R)-nerolidyl diphosphate (NPP), ionization of NPP, and C-1,C-6-ring closure to generate a bisabolyl cation, followed by a 1,3-hydride shift, 1,10-ring closure to generate the amorphane skeleton, and deprotonation at either C-12 or C-13 to afford the final product (1S,6R,7R,10R)-amorpha-4,11-diene.
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α-Bisabolol has been found as a minor product from the enzyme amorpha-4,11-diene synthase from A. annua.
“The bisabolane sesquiterpene, α-bisabolol (385), has been found as a minor product from the enzyme amorpha-4,11-diene synthase from A. annua (Section 2.6.3) [136].”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [136]
The mechanism of ADS-catalysed cyclization of FPP involves isomerization to nerolidyl diphosphate, C-1,C-6-ring closure to a bisabolyl cation, a 1,3-hydride shift, second ring closure between 1- and 10-positions to generate the amorphane skeleton, and deprotonation at C-12 or C-13 to afford amorpha-4,11-diene.
“It is proposed that FPP is first isomerized to nerolidyl diphosphate; ionization of nerolidyl pyrophosphate is followed by C-1,C-6-ring closure to generate a bisabolyl cation; next, this cation undergoes a 1,3-hydride shift [295] permitting a second ring closure between the 1- and 10-positions to generate the amorphane skeleton; and, finally, deprotonation at either C-12 or C-13 affords amorpha-4,”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [136]
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“…such as amorpha-4,11-diene synthase (ADS), amorphadiene 12-hydroxylase (the cytochrome P450 71AV1 [CYP71AV1]), artemisinic aldehydeΔ11(13) reductase (double bond reductase 2 [DBR2]) and aldehyde dehydrogenase 1 (ALDH1) (Picaud et al. 2006; Zhang et al. 2008; Teoh et al. 2009; Rydén et al. 2010).”
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“Cyclisation of FPP into this sesquiterpene likely occurs via the bisabolyl cation 75 , similar to the endogenous β -chamigrene 76 , therefore we expected this structural similarity to enable amorpha-4,11-diene transport into OBs.”
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“…(NPP), ionization of NPP, and C 1 , C 6 ring closure to generate a bisabolyl cation, which is followed by a 1,3-hydride shift, 1,10-ring closure generating the amorphane skeleton, and deprotonation at either C 12 or C 13 into the final product (1S,6R,7R,10R)-amorpha-4,11-diene (Picaud et al. 2006).”
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“In artemisinin biosynthesis, AaADS is a sesquiterpene synthase controlling the first step cyclization of FPP to amorpha-4,11-diene via a twostep cyclization (1,6- and subsequent 1,10-ring closure) following by a regioselective deprotonation (Kim et al. 2006; Picaud et al. 2006; Figure 5).”
BackgroundMetabolomics-Based Studies on Artemisinin Biosynthesis
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- Authors
- Picaud, S., Mercke, P., He, X., Sterner, O., Brodelius, M., Cane, D. E., & Brodelius, P. E.
- Affiliations
- Brown University (US)
- Lund University (SE)
- Corresponding author
- Brodelius, Peter E.
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 448
- Issue
- 1-2
- Pages
- 150-155
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W1996311074
- Cited by
- 79
- References
- 22
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 12 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 5
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM 30301)
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Keywords
- amorpha-4,11-diene synthase, stereochemistry, deuterium labeling, 1,3-hydride shift, Artemisia annua, sesquiterpene biosynthesis
- MeSH terms
- Enzyme Activation, Escherichia coli, Polyisoprenyl Phosphates, Recombinant Proteins, Sesquiterpenes, Stereoisomerism, Alkyl and Aryl Transferases, Artemisia annua
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