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1.
Artemisinin isolated from the aerial parts of Artemisia annua L. is a promising and potent antimalarial drug which has a remarkable activity against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum, and is useful in treatment of cerebral malaria. Because the low content (0.01–1 %) of artemisinin in A. annua is a limitation to the commercial production of the drug, many research groups have been focusing their researches on enhancing the production of artemisinin in tissue culture or in the whole plant of A. annua. This review mainly focuses on the progresses made in the production of artemisinin from A. annua by biotechnological strategies including in vitro tissue culture, metabolic regulation of artemisinin biosynthesis, genetic engineering, and bioreactor technology. 相似文献
2.
Moran Farhi Magali Kozin Shai Duchin 《Biotechnology & genetic engineering reviews》2013,29(2):135-148
Artemisinin, a natural compound from Artemisia annua, is highly effective in treating drug-resistant malaria. Because chemical synthesis of this natural terpenoid is not economically feasible, its only source remains as the native plant which produces only small quantities of it, resulting in a supply that is far short of demand. Extensive efforts have been invested in metabolic engineering for the biosynthesis of artemisinin precursors in microbes. However, the production of artemisinin itself has only been achieved in plants. Since, A. annua possesses only poorly developed genetic resources for traditional breeders, molecular breeding is the best alternative. In this review, we describe the efforts taken to enhance artemisinin production in A. annua via transgenesis and advocate metabolic engineering of the complete functional artemisinin metabolic pathway in heterologous plants. In both cases, we emphasize the need to apply state-of-the-art synthetic biology approaches to ensure successful biosynthesis of the drug. 相似文献
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《Journal of Plant Interactions》2013,8(1):655-665
Artemisinin, a natural product isolated from aerial parts of Artemisia annua L. plant, is a potent antimalarial drug against drug-resistant malaria. In recent times, the demand (101–119 MT) for artemisinin is exponentially increasing with the increased incidence of drug-resistant malaria throughout the world, especially African and Asian continents. However, the commercial production of artemisinin-based combination therapies has limitation because of the presence of low concentration of artemisinin in plants. Therefore, transgenic lines of A. annua L. plants over-expressing both HMG-Co A reductase (hmgr) and amorpha-4, 11-diene synthase (ads) genes were developed to enhance the content of artemisinin. The selected transgenic lines (TR4, TR5, and TR7) were found to accumulate higher artemisinin (0.97–1.2%) as compared to the non-transgenic plants (0.63%). The secondary metabolite profiles of these lines were also investigated employing gas chromatography mass spectrometry, which revealed a clear difference in these metabolites in transgenic and non-transgenic lines of A. annua L. at different growth and developmental stages. The major metabolites reported in these lines at pre-flowering stage were related to essential oil and chlorophyll biosynthesis (71.33% in TR5 transgenic lines vs. 61.70% in non-transgenic line). Based on these results, we concluded that over-expression of both hmgr and ads genes in A. annua L. plants results not only increase in artemisinin content, but also enhances synthesis of other isoprenoid including essential oil. It is also evident from this study that the novel artemisinin-rich varieties of A. annua L. could be developed by suppressing essential oil biosynthesis, so that more carbon could preferentially be diverted from mevalonate pathway to artemisinin biosynthesis. 相似文献
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Fuyuan Jing Ling Zhang Meiya Li Yueli Tang Yuliang Wang Yueyue Wang Quan Wang Qifang Pan Guofeng Wang Kexuan Tang 《Biologia》2009,64(2):319-323
Artemisinin, a sesquiterpene lactone endoperoxide derived from Artemisia annua L., is the most effective antimalarial drug. In an effort to increase the artemisinin production, abscisic acid (ABA) with
different concentrations (1, 10 and 100 μM) was tested by treating A. annua plants. As a result, the artemisinin content in ABA-treated plants was significantly increased. Especially, artemisinin content
in plants treated by 10 μM ABA was 65% higher than that in the control plants, up to an average of 1.84% dry weight. Gene
expression analysis showed that in both the ABA-treated plants and cell suspension cultures, HMGR, FPS, CYP71AV1 and CPR, the important genes in the artemisinin biosynthetic pathway, were significantly induced. While only a slight increase of
ADS expression was observed in ABA-treated plants, no expression of ADS was detected in cell suspension cultures. This study suggests that there is probably a crosstalk between the ABA signaling
pathway and artemisinin biosynthetic pathway and that CYP71AV1, which was induced most significantly, may play a key regulatory role in the artemisinin biosynthetic pathway. 相似文献
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Artemisinin is a promising and potent antimalarial drug naturally produced by the plant Artemisia annua L. but in very low yield. Its artemisinin content is known to be greatly affected by both genotype and environmental factors.
In this study, the production of artemisinin and leaf biomass in Artemisia annua L. was significantly increased by exogenous GA3 treatment. The effect of GA3 application on expression of proposed key enzymes involved in artemisinin yield was examined in both wild type (007) and
FPS-overexpression (253-2) lines of A. annua. In the wild type (007) at 6 h post GA3 application there was an abrupt rise in FPS, ADS and CYP71AV1 expression and at 24 h a temporary and significant peak in artemisinin (1.45-fold higher than the control). After GA3 application in line 253-2, there was a dramatic rise in expression of FPS at 3 h, CYP71AV1 at 9 h and ADS at 72 h and accumulation of artemisinin after 7 days, which was a delay when compared with the wild type plant. Thus, increased
artemisinin content from exogenous GA3 treatment was associated with increased expression of key enzymes in the artemisinin biosynthesis pathway. Interestingly,
exogenous GA3 continuously enhanced artemisinin content from the vegetative stage to flower initiation in both plant lines and gave significantly
higher leaf biomass than in control plants. Consequently, the artemisinin yield in GA3-treated plants was much higher than in control plants. Although the maximum artemisinin content was found at the full blooming
stage [2.1% dry weight (DW) in 007 and 2.4% DW in 253-2], the highest artemisinin yield in GA3-treated plants was obtained during the flower initiation stage (2.4 mg/plant in 007 and 2.3 mg/plant in 235-2). This was
26.3 and 27.8% higher, respectively, than in non-treated plants 007 and 253-2. This study showed that exogenous GA3 treatment enhanced artemisinin production in pot experiments and should be suitable for field application. 相似文献
9.
Gao-Jie Hong Wen-Li Hu Jian-Xu Li Xiao-Ya Chen Ling-Jian Wang 《Plant Molecular Biology Reporter》2009,27(3):334-341
10.
Boron is an essential plant micronutrient, but it is phytotoxic if present in excessive amounts in soil for certain plants
such as Artemisia annua L. that contains artemisinin (an important antimalarial drug) in its areal parts. Artemisinin is a sesquiterpene lactone
with an endoperoxide bridge. It is quite expensive compound because the only commercial source available is A. annua and the compound present in the plant is in very low concentration. Since A. annua is a major source of the antimalarial drug and B stress is a deadly threat to its cultivation, the present research was conducted
to determine whether the exogenous application of methyl jasmonate (MeJA) could combat the ill effects of excessive B present
in the soil. According to the results obtained, the B toxicity induced oxidative stress and reduced the stem height as well
as fresh and dry masses of the plant remarkably. The excessive amounts of soil B also lowered the net photosynthetic rate,
stomatal conductance, internal CO2 concentration and total chlorophyll content in the leaves. In contrast, the foliar application of MeJA enhanced the growth
and photosynthetic efficiency both in the stressed and non-stressed plants. The excessive B levels also increased the activities
of antioxidant enzymes, such as catalase, peroxidase and superoxide dismutase. Endogenous H2O2 and O2− levels were also high in the stressed plants. However, the MeJA application to the stressed plants reduced the amount of
lipid peroxidation and stimulated the synthesis of antioxidant enzymes, enhancing the content and yield of artemisinin as
well. Thus, it was concluded that MeJA might be utilized in mitigating the B toxicity and improving the content and yield
of artemisinin in A. annua plant. 相似文献
11.
Artemisinin, the endoperoxide sesquiterpene lactone, is an effective antimalarial drug isolated from the Chinese medicinal plant Artemisia annua L. Due to its effectiveness against multi-drug-resistant cerebral malaria, it becomes the essential components of the artemisinin-based combination therapies which are recommended by the World Health Organization as the preferred choice for malaria tropica treatments. To date, plant A. annua is still the main commercial source of artemisinin. Although semi-synthesis of artemisinin via artemisinic acid in yeast is feasible at present, another promising approach to reduce the price of artemisinin is using plant metabolic engineering to obtain a higher content of artemisinin in transgenic plants. In the past years, an Agrobacterium-mediated transformation system of A. annua has been established by which a number of genes related to artemisinin biosynthesis have been successfully transferred into A. annua plants. In this review, the progress on increasing artemisinin content in A. annua by transgenic approach and its future prospect are summarized and discussed. 相似文献
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Artemisinin, an endoperoxidized sesquiterpene originally extracted from the medicinal plant Artemisia annua L., is a potent malaria-killing agent. Due to the urgent demand and short supply of this new antimalarial drug, engineering
enhanced production of artemisinin by genetically-modified or transgenic microbes is currently being explored. Cloning and
expression of the artemisinin biosynthetic genes in Saccharomyces
cerevisiae and Escherichia coli have led to large-scale microbial production of the artemisinin precursors such as amorpha-4,11-diene and artemisinic acid.
Although reconstruction of the complete biosynthetic pathway toward artemisinin in transgenic yeast and bacteria has not been
achieved, artemisinic acid available from these transgenic microbes facilitates the subsequent partial synthesis of artemisinin
by either chemical or biotransformational process, thereby providing an attractive strategy alternative to the direct extraction
of artemisinin from A.annua L. In this review, we update the current trends and summarize the future prospects on genetic engineering of the microorganisms
capable of accumulating artemisinin precursors through heterologous and functional expression of the artemisinin biosynthetic
genes. 相似文献
14.
Annual wormwood (Artemisia annua L.) produces an array of complex terpenoids including artemisinin, a compound of current interest in the treatment of drug-resistant
malaria. However, this promising antimalarial compound remains expensive and is hardly available on the global scale. Synthesis
of artemisinin has not been proved to be feasible commercially. Therefore, increase in yield of naturally occurring artemisinin
is an important area of investigation. The effects of inoculation by two arbuscular mycorrhizal (AM) fungi, Glomus macrocarpum and Glomus fasciculatum, either alone or supplemented with P-fertilizer, on artemisinin concentration in A. annua were studied. The concentration of artemisinin was determined by reverse-phase high-performance liquid chromatography with
UV detection. The two fungi significantly increased concentration of artemisinin in the herb. Although there was significant
increase in concentration of artemisinin in nonmycorrhizal P-fertilized plants as compared to control, the extent of the increase
was less compared to mycorrhizal plants grown with or without P-fertilization. This suggests that the increase in artemisinin
concentration may not be entirely attributed to enhanced P-nutrition and improved growth. A strong positive linear correlation
was observed between glandular trichome density on leaves and artemisinin concentration. Mycorrhizal plants possessed higher
foliar glandular trichome (site for artemisinin biosynthesis and sequestration) density compared to nonmycorrhizal plants.
Glandular trichome density was not influenced by P-fertilizer application. The study suggests a potential role of AM fungi
in improving the concentration of artemisinin in A. annua. 相似文献
15.
The stacked over-expression of FPS, CYP71AV1 and CPR genes leads to the increase of artemisinin level in Artemisia annua L. 总被引:1,自引:0,他引:1
Yunfei Chen Qian Shen Yueyue Wang Tao Wang Shaoyan Wu Ling Zhang Xu Lu Fangyuan Zhang Weimin Jiang Bo Qiu Erdi Gao Xiaofen Sun Kexuan Tang 《Plant biotechnology reports》2013,7(3):287-295
Artemisinin is an endoperoxide sesquiterpene lactone isolated from the aerial parts of Artemisia annua L., and is presently the most potent anti-malarial drug. Owing to the low yield of artemisinin from A. annua as well as the widespread application of artemisinin-based combination therapy recommended by the World Health Organization, the global demand for artemisinin is substantially increasing and is therefore rendering artemisinin in short supply. An economical way to increase artemisinin production is to increase the content of artemisinin in A. annua. In this study, three key genes in the artemisinin biosynthesis pathway, encoding farnesyl diphosphate synthase, amorpha-4, 11-diene C-12 oxidase and its redox partner cytochrome P450 reductase, were over-expressed in A. annua through Agrobacterium-mediated transformation. The transgenic lines were confirmed by Southern blotting and the over-expressions of the genes were demonstrated by real-time PCR assays. The HPLC analysis showed that the artemisinin contents in transgenic lines were increased significantly, with the highest one found to be 3.6-fold higher (2.9 mg/g FW) than that of the control. These results demonstrate that multigene engineering is an effective way to enhance artemisinin content in A. annua. 相似文献
16.
Artemisinin, a sesquiterpene lactone isolated from the Chinese medicinal plant Artemisia annua L., is an effective antimalarial agent, especially for multi-drug resistant and cerebral malaria. To date, A. annua is still the only commercial source of artemisinin. The low concentration of artemisinin in A. annua, ranging from 0.01 to 0.8% of the plant dry weight, makes artemisinin relatively expensive and difficult to meet the demand
of over 100 million courses of artemisinin-based combinational therapies per year. Since the chemical synthesis of artemisinin
is not commercially feasible at present, another promising approach to reduce the price of artemisinin-based antimalarial
drugs is metabolic engineering of the plant to obtain a higher content of artemisinin in transgenic plants. In the past decade,
we have established an Agrobacterium-mediated transformation system of A. annua, and have successfully transferred a number of genes related to artemisinin biosynthesis into the plant. The various aspects
of these efforts are discussed in this review. 相似文献
17.
Pamela J. Weathers Patrick R. Arsenault Patrick S. Covello Anthony McMickle Keat H. Teoh Darwin W. Reed 《Phytochemistry Reviews》2011,10(2):173-183
Artemisia annua L. produces the sesquiterpene lactone, artemisinin, a potent antimalarial drug that is also effective in treating other parasitic
diseases, some viral infections and various neoplasms. Artemisinin is also an allelopathic herbicide that can inhibit the
growth of other plants. Unfortunately, the compound is in short supply and thus, studies on its production in the plant are
of interest as are low cost methods for drug delivery. Here we review our recent studies on artemisinin production in A. annua during development of the plant as it moves from the vegetative to reproductive stage (flower budding and full flower formation),
in response to sugars, and in concert with the production of the ROS, hydrogen peroxide. We also provide new data from animal
experiments that measured the potential of using the dried plant directly as a therapeutic. Together these results provide
a synopsis of a more global view of regulation of artemisinin biosynthesis in A. annua than previously available. We further suggest an alternative low cost method of drug delivery to treat malaria and other
neglected tropical diseases. 相似文献
18.
The potent antimalarial sesquiterpene lactone, artemisinin, is produced in low quantities by the plant Artemisia annua L. The source and regulation of the isopentenyl diphosphate (IPP) used in the biosynthesis of artemisinin has not been completely
characterized. Terpenoid biosynthesis occurs in plants via two IPP-generating pathways: the mevalonate pathway in the cytosol,
and the non-mevalonate pathway in plastids. Using inhibitors specific to each pathway, it is possible to resolve which supplies
the IPP precursor to the end product. Here, we show the effects of inhibition on the two pathways leading to IPP for artemisinin
production in plants. We grew young (7–14 days post cotyledon) plants in liquid culture, and added mevinolin to the medium
to inhibit the mevalonate pathway, or fosmidomycin to inhibit the non-mevalonate pathway. Artemisinin levels were measured
after 7–14 days incubation, and production was significantly reduced by each inhibitor compared to controls, thus, it appears
that IPP from both pathways is used in artemisinin production. Also when grown in miconazole, an inhibitor of sterol biosynthesis,
there was a significant increase in artemisinin compared to controls suggesting that carbon was shifted from sterols into
sesquiterpenes. Collectively these results indicate that artemisinin is probably biosynthesized from IPP pools from both the
plastid and the cytosol, and that carbon from competing pathways can be channeled toward sesquiterpenes. This information
will help advance our understanding of the regulation of in planta production of artemisinin. 相似文献
19.
Ling Zhang Xu Lu Qian Shen Yunfei Chen Tao Wang Fangyuan Zhang Shaoyan Wu Weimin Jiang Pin Liu Lida Zhang Yueyue Wang Kexuan Tang 《Plant Molecular Biology Reporter》2012,30(4):838-847
Artemisinin has attracted interest due to its medicinal value in treating malaria and its potential for use against certain cancers and viral diseases. Trichome density and capacity determine artemisinin content in Artemisia annua plants. Thus, the ATP-binding cassette transporter G (ABCG) subfamily involved in trichome cuticle development may also influence artemisinin accumulation. In this study, putative A. annua ABC transporter unigenes were identified and classified from the unigene sequences up to date in the National Center for Biotechnology Information database, and nine putative A. annua ABCG transporter unigenes that may be involved in cuticle development were selected for expression analyses. Two of them, AaABCG6 and AaABCG7, showed parallel expression pattern as two artemisinin biosynthesis-specific genes (amorpha-4, 11-diene synthase and a cytochrome P450-dependent hydroxylase, CYP71AV1) in different tissues and different leaf development stages and also showed similar induction in the plants after methyl jasmonate or abscisic acid treatments. Identification of these putative A. annua ABCG transporter unigenes could provide the basis for cloning of the full-length genes and further functional investigation to find the artemisinin relevant transporters, which could be used for improving artemisinin yield in both A. annua plants and heterologous systems using transgenic technology. 相似文献
20.
Mostafa A. Elfawal Melissa J. Towler Nicholas G. Reich Douglas Golenbock Pamela J. Weathers Stephen M. Rich 《PloS one》2012,7(12)
Drugs are primary weapons for reducing malaria in human populations. However emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that is developed and deployed. Currently the most effective anti-malarial is artemisinin, which is extracted from the leaves of Artemisia annua. Due to poor pharmacokinetic properties and prudent efforts to curtail resistance to monotherapies, artemisinin is prescribed only in combination with other anti-malarials composing an Artemisinin Combination Therapy (ACT). Low yield in the plant, and the added cost of secondary anti-malarials in the ACT, make artemisinin costly for the developing world. As an alternative, we compared the efficacy of oral delivery of the dried leaves of whole plant (WP) A. annua to a comparable dose of pure artemisinin in a rodent malaria model (Plasmodium chabaudi). We found that a single dose of WP (containing 24 mg/kg artemisinin) reduces parasitemia more effectively than a comparable dose of purified drug. This increased efficacy may result from a documented 40-fold increase in the bioavailability of artemisinin in the blood of mice fed the whole plant, in comparison to those administered synthetic drug. Synergistic benefits may derive from the presence of other anti-malarial compounds in A. annua. If shown to be clinically efficacious, well-tolerated, and compatible with the public health imperative of forestalling evolution of drug resistance, inexpensive, locally grown and processed A. annua might prove to be an effective addition to the global effort to reduce malaria morbidity and mortality. 相似文献