In vivo transformations of dihydroartemisinic acid in Artemisia annua plants

Brown, Geoffrey D; Sy, Lai-King

doi:10.1016/j.tet.2003.11.070

Cited by 183Plant biochemistry and biosynthesisSesquiterpenes and Asteraceae StudiesPlant tissue culture and regeneration

In vivo transformations of dihydroartemisinic acid in Artemisia annua plants

Brown, Geoffrey D, Sy, Lai-King·2004·Tetrahedron

DOI 10.1016/j.tet.2003.11.070

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The final steps in the conversion of DHAA to artemisinin are considered to be non-enzymatic and may be extracellular.
“the final steps in the conversion of DHAA to artemisinin are considered to be non-enzymatic and may be extracellular (17, 18).”
From Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [17]
In vivo and in vitro formation of low abundance by-products derived from other intermediates of artemisinin synthesis have previously been reported.
“In vivo and in vitro formation of low abundance by-products derived from other intermediates of artemisinin synthesis have previously been reported (12, 17, 18).”
From Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [17]
The DHAAOOH intermediate can also give rise to both dihydroepideoxyarteannuin B (DHEDB) and (by Hock-cleavage) deoxyartemisinin.
“Previous work has shown that the DHAAOOH intermediate can also give rise to both dihydroepideoxyarteannuin B (DHEDB) (31), and (by Hock-cleavage) deoxyartemisinin (17).”
From Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [17]
Arteannuin X might be biosynthesised from A-4,11-D via its tertiary hydroperoxide (A-4,11-DOOH) in vivo, in much the same way that DHAA has previously been shown to be transformed to artemisinin via DHAAOOH.
“This provided the first circumstantial evidence that arteannuin X might be biosynthesised from A4,11-D via its tertiary hydroperoxide (A-4,11-DOOH) in vivo , in much the same way that DHAA has previously been shown to be transformed to artemisinin via the tertiary allylic hydroperoxide of dihydroartemisinic acid, DHAAOOH (17).”
From Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [17]
DHAAOOH cannot efficiently undergo Hock-cleavage into artemisinin in an aqueous environment and may preferentially form DHEDB.
“as previous results have indicated that DHAAOOH cannot efficiently undergo Hock-cleavage into artemisinin in an aqueous environment (such as trichome extraction buffer), and that it may preferentially form DHEDB (17).”
From Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [17]

There is strong in vivo and in vitro evidence that DHAA undergoes non-enzymatic autoxidation to DHAAOOH and subsequent nonenzymatic rearrangement to artemisinin.
“There is strong in vivo and in vitro evidence for a non-enzymatic autoxidation of DHAA to DHAAOOH and subsequent nonenzymatic rearrangement to artemisinin (17).”
From Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [17]
The conversion of dihydroartemisinic acid to artemisinin is believed to be a non-enzymatic spontaneous reaction.
“The conversion of dihydroartemisinic acid to artemisinin is believed to be a non-enzymatic spontaneous reaction [14].”
From Relative expression of genes of terpene metabolism in different tissues of Artemisia annuaL (2011) · cites this paper as [14]
Dihydroartemisinic acid, not artemisinic acid, is the precursor of artemisinin.
“recent feeding experiments with artemisinic acid [13] and dihydroartemisinic acid [14] have shown that the latter substance is the precursor of artemisinin.”
From Relative expression of genes of terpene metabolism in different tissues of Artemisia annuaL (2011) · cites this paper as [14]
Feeding labelled dihydroartemisinic acid (480) to A. annua resulted in sixteen labelled amorphane and cadinane sesquiterpenes, including all nine of the 11,13-dihydro forms in the pairs in Table 37.
“Feeding labelled dihydroartemisinic acid (480) to A. annua resulted in sixteen labelled amorphane and cadinane sesquiterpenes [185], which included all nine of the 11,13-dihydro forms in the “pairs” in Table 37”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
The most significant products from the feeding study with labelled dihydroartemisinic acid were dihydroarteannuin B (479), dihydro-epi-deoxyarteannuin B (485) and the dihydro seco-cadinane (493).
“* The most significant products from this feeding study were dihydroarteannuin B (479), dihydro-epi-deoxyarteannuin B (485) and the dihydro seco-cadinane (493).”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
Feeding experiments with both labeled precursors appear to show that artemisinic acid (473) and dihydroartemisinic acid (480) are not mutually interconvertible.
“In addition, feeding experiments with both labeled precursors appear to show that artemisinic acid (473) and dihydroartemisinic acid (480) are NOT mutually interconvertible”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
The biological transformations of (473)/(480) have been proposed to involve spontaneous autoxidation of the Δ4,5 double bond and subsequent rearrangements of the resultant allylic hydroperoxides.
“These biological transformations have been proposed to involve spontaneous autoxidation of the Δ4,5 double bond in (473)/(480) and subsequent rearrangements of the resultant allylic hydroperoxides [155,185].”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
There is no interconversion in either direction between artemisinic acid (473) and dihydroartemisinic acid (480).
“and more recent biosynthetic studies, employing both labeled artemisinic acid [155] and dihydroartemisinic acid [185], have confirmed that there is no interconversion in either direction between dihydroartemisinic acid (473) and artemisinic acid (480)”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
The tertiary allylic hydroperoxide 481 is a biosynthetic intermediate linking dihydroartemisinic acid (480) and artemisinin (495), as shown by in vivo experiments with labeled dihydroartemisinic acid (480).
“The tertiary allylic hydroperoxide 481, which is produced in step i), has already been shown to be a biosynthetic intermediate, linking dihydroartemisinic acid (480) and artemisinin (495), by in vivo experiments with labeled dihydroartemisinic acid (480) [185,189].”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
The final transformations to artemisinin (495) in phase 3 may be non-enzymatic, supported by in vivo and in vitro studies under conditions relevant to the living plant.
“The proposal that the final transformations to artemisinin (495) in phase 3 may be non-enzymatic also receives strong support both from in vivo studies [168,185] and from experiments which have been performed in vitro [167,193,218], under conditions that are relevant to the living plant.”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
Dihydroartemisinic acid (480) is a precursor to artemisinin (495) in A. annua.
“The experimental conditions for this study were purposely chosen to allow comparison with a previous investigation, which had demonstrated that dihydroartemisinic acid [15-[2H313C]-(480)] was a precursor to artemisinin (495)) [185]”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]
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 [185]
Artemisinic acid (473) is not a precursor to dihydroartemisinic acid (480).
“given that it seems now to be proven that artemisinic acid (473) is not a precursor to dihydroartemisinic acid (480) (see crossed arrow in Scheme 11) [155,185]”
From The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao) (2010) · cites this paper as [185]

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Artemisia absinthium L. Artemisia annua L. Artemisia dracunculus L. Artemisia leucodes Schrenk Artemisia scoparia Waldst. & Kit. Artemisia vulgaris L. Eclipta prostrata (L.) L. Asteraceae
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Authors: Brown, G. D., & Sy, L.-K.
Affiliations: University Grants Committee (HK)
Corresponding author: Brown, Geoffrey D
ORCID: Brown, Geoffrey D
Venue: Tetrahedron
Publisher: Elsevier BV
Published: 2004-01
Volume: 60
Issue: 5
Pages: 1139-1159
ISSN: 0040-4020 (ISSN-L)
DOI: 10.1016/j.tet.2003.11.070
OpenAlex: W2162903401
Cited by: 183
References: 64
Citations by year: 2026: 2 · 2025: 6 · 2024: 12 · 2023: 9 · 2022: 5 · 2021: 8 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 23 · 2015: 12 · 2014: 10 · 2013: 12 · 2012: 8
FWCI: 0.54
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Tetrahedron (publishedVersion)
CentAUR (University of Reading) (submittedVersion)
The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders: University of Hong Kong
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: dihydroartemisinic acid, Artemisia annua, in vivo metabolism, cadinane sesquiterpenes, allylic hydroperoxides, autoxidation, plant secondary metabolites

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