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Review
. 2010 Oct 28;15(11):7603-98.
doi: 10.3390/molecules15117603.

The biosynthesis of artemisinin (Qinghaosu) and the phytochemistry of Artemisia annua L. (Qinghao)

Affiliations
Review

The biosynthesis of artemisinin (Qinghaosu) and the phytochemistry of Artemisia annua L. (Qinghao)

Geoffrey D Brown. Molecules. .

Abstract

The Chinese medicinal plant Artemisia annua L. (Qinghao) is the only known source of the sesquiterpene artemisinin (Qinghaosu), which is used in the treatment of malaria. Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product. The phytochemistry of A. annua is dominated by both sesquiterpenoids and flavonoids, as is the case for many other plants in the Asteraceae family. However, A. annua is distinguished from the other members of the family both by the very large number of natural products which have been characterised to date (almost six hundred in total, including around fifty amorphane and cadinane sesquiterpenes), and by the highly oxygenated nature of many of the terpenoidal secondary metabolites. In addition, this species also contains an unusually large number of terpene allylic hydroperoxides and endoperoxides. This observation forms the basis of a proposal that the biogenesis of many of the highly oxygenated terpene metabolites from A. annua - including artemisinin itself - may proceed by spontaneous oxidation reactions of terpene precursors, which involve these highly reactive allyllic hydroperoxides as intermediates. Although several studies of the biosynthesis of artemisinin have been reported in the literature from the 1980s and early 1990s, the collective results from these studies were rather confusing because they implied that an unfeasibly large number of different sesquiterpenes could all function as direct precursors to artemisinin (and some of the experiments also appeared to contradict one another). As a result, the complete biosynthetic pathway to artemisinin could not be stated conclusively at the time. Fortunately, studies which have been published in the last decade are now providing a clearer picture of the biosynthetic pathways in A. annua. By synthesising some of the sesquiterpene natural products which have been proposed as biogenetic precursors to artemisinin in such a way that they incorporate a stable isotopic label, and then feeding these precursors to intact A. annua plants, it has now been possible to demonstrate that dihydroartemisinic acid is a late-stage precursor to artemisinin and that the closely related secondary metabolite, artemisinic acid, is not (this approach differs from all the previous studies, which used radio-isotopically labelled precursors that were fed to a plant homogenate or a cell-free preparation). Quite remarkably, feeding experiments with labeled dihydroartemisinic acid and artemisinic acid have resulted in incorporation of label into roughly half of all the amorphane and cadinane sesquiterpenes which were already known from phytochemical studies of A. annua. These findings strongly support the hypothesis that many of the highly oxygenated sesquiterpenoids from this species arise by oxidation reactions involving allylic hydroperoxides, which seem to be such a defining feature of the chemistry of A. annua. In the particular case of artemisinin, these in vivo results are also supported by in vitro studies, demonstrating explicitly that the biosynthesis of artemisinin proceeds via the tertiary allylic hydroperoxide, which is derived from oxidation of dihydroartemisinic acid. There is some evidence that the autoxidation of dihydroartemisinic acid to this tertiary allylic hydroperoxide is a non-enzymatic process within the plant, requiring only the presence of light; and, furthermore, that the series of spontaneous rearrangement reactions which then convert this allylic hydroperoxide to the 1,2,4-trioxane ring of artemisinin are also non-enzymatic in nature.

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Figures

Figure 1
Figure 1
Artemisinin and its semi-synthetic derivatives, which are currently used in the treatment of malaria.
Figure 2
Figure 2
Structures of isopentenyl pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate (GPP), neryl pyrophosphate (NPP) and linaloyl pyrophosphate (LPP) which are all possible precursors to monoterpenes from A.annua.
Scheme 1
Scheme 1
Postulated biosynthesis of allylic hydroperoxides: α-myrcene hydroperoxide (265) and β-myrcene hydroperoxide (264) via spontaneous autoxidation reactions at the tri-substituted bond of the precursor myrcene (254). Further reactions of such allylic hydroperoxides would account for the biogenesis of oxygenated monoterpenes such as (267), (263), (271) and (272).
Scheme 2
Scheme 2
Formation of the irregular artemisyl, lavandulyl and santolinyl skeletons in A. annua by “head-to-middle” condensation of a DMAPP (C5) precursor and subsequent carbon-carbon cleavage reactions of the resulting intermediate, chryanthemyl pyrophosphate.
Scheme 3
Scheme 3
Proposed formation of lavandulanes 279 and 280 by spontaneous autoxidation reactions.
Scheme 4
Scheme 4
Postulated biogenesis of (414) and (413) by spontaneous autoxidation reaction of (422), followed by reduction.
Scheme 5
Scheme 5
Proposed biogenesis of arteannuin H (465) and other amorphane sesquiterpenes from A. annua via tertiary and allylic secondary hydroperoxides which are derived from spontaneous autoxidation of dihydroartemisinic acid (480)/artemisinic acid (473).
Scheme 6
Scheme 6
The most dominant products from metabolism of dihydroartemisinic acid (480) in vivo in A. annua plants.
Scheme 7
Scheme 7
The most dominant products from metbolism of artemisinic acid (473) in vivo in A. annua plants.
Scheme 8
Scheme 8
Proposed formation of phytene-1-ol-2-hydroperoxide (553) by spontaneous autoxidation of phytol (550) and subsequent homolysis/reduction of 553 to phytene-1,2-diol (552).
Scheme 9
Scheme 9
Three phases in the biosynthesis of artemisinin (495).
Scheme 10
Scheme 10
Cyclization of FPP (378) to amorpha-4,11-diene (451), catalysed by the enzyme ADS.
Figure 3
Figure 3
Minor products from the cyclization of FPP (378) by ADS, which have not yet been reported as natural products from A. annua. Amorph-4-en-11-ol (574) is probably formed by quenching of the C-11 amorphane cation by water; β-sesquiphellandrene (575) by elimination of H-15 from the C-1 bisabolyl cation; zingiberene (576) from elimination of H-4 from the C-1 biasabolyl cation; zingiberenol (577) by quenching of the allylic C-1 bisabolyl cation by water; and γ-humulene (578) by an alternative cyclization of nerolidyl pyrophosphate.
Scheme 11
Scheme 11
Various possible routes for the oxidation of the isopropylidene group in amorpha-4,11-diene (451), yielding artemisinic acid (473) and/or dihydroartemisinic acid (480) in phase 2 of the biosynthesis of artemisinin.
Scheme 12
Scheme 12
A four-step mechanism for the spontaneous autoxidation of dihydroartemisinic acid (480) to artemisinin (495) in A. annua.
Figure 4
Figure 4
Metabolites which have been isolated from tissue culture of A.annua, but which have not yet been reported from A. annua plants.
Scheme 13
Scheme 13
Genetic engineering of enzymes for the production of artemisinic acid (473) from A. annua in to a microbial host.

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