Artemisia annua glandular secretory trichomes: the biofactory of antimalarial agent artemisinin

Xiao, Ling; Tan, Hexin; Zhang, Lei

doi:10.1007/s11434-015-0980-z

Cited by 76 publications

(55 citation statements)

References 75 publications

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“…Glandular trichomes are the localization of the artemisinin biosynthesis ( Duke et al, 1994 ; Xiao et al, 2016 ). A field study reported that application of salicylic acid or chitosan oligosaccharidea (out of different stress treatments) could significantly decrease 4–9 glandular trichomes per square of millimeter only on upper leaves from mature plants grown in the field ( Kjaer et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Artemisia annua Cinnamyl Alcohol Dehydrogenase Increases Lignin and Coumarin and Reduces Artemisinin and Other Sesquiterpenes

Alejos-González

et al. 2018

Front. Plant Sci.

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Artemisia annua is the only medicinal crop that produces artemisinin for malarial treatment. Herein, we describe the cloning of a cinnamyl alcohol dehydrogenase (AaCAD) from an inbred self-pollinating (SP) A. annua cultivar and its effects on lignin and artemisinin production. A recombinant AaCAD was purified via heterogeneous expression. Enzyme assays showed that the recombinant AaCAD converted p-coumaryl, coniferyl, and sinapyl aldehydes to their corresponding alcohols, which are key intermediates involved in the biosynthesis of lignin. Km, Vmax, and Vmax/Km values were calculated for all three substrates. To characterize its function in planta, AaCAD was overexpressed in SP plants. Quantification using acetyl bromide (AcBr) showed significantly higher lignin contents in transgenics compared with wild-type (WT) plants. Moreover, GC-MS-based profiling revealed a significant increase in coumarin contents in transgenic plants. By contrast, HPLC-MS analysis showed significantly reduced artemisinin contents in transgenics compared with WT plants. Furthermore, GC-MS analysis revealed a decrease in the contents of arteannuin B and six other sesquiterpenes in transgenic plants. Confocal microscopy analysis showed the cytosolic localization of AaCAD. These data demonstrate that AaCAD plays a dual pathway function in the cytosol, in which it positively enhances lignin formation but negatively controls artemisinin formation. Based on these data, crosstalk between these two pathways mediated by AaCAD catalysis is discussed to understand the metabolic control of artemisinin biosynthesis in plants for high production.

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Section: Discussionmentioning

confidence: 99%

Overexpression of Artemisia annua Cinnamyl Alcohol Dehydrogenase Increases Lignin and Coumarin and Reduces Artemisinin and Other Sesquiterpenes

Alejos-González

et al. 2018

Front. Plant Sci.

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“…These compounds can defend plants against pathogens and pests, and they have considerable commercial value (Wagner, 1991). Thus, glandular trichomes are considered as true cell biofactories for the production of valuable chemicals, thereby making them suitable targets for metabolic engineering and breeding (Schilmiller et al, 2008;Tissier, 2012;Xiao et al, 2016). Consequently, significant efforts are required to improve their productivity, for example, by increasing glandular trichome density (Tissier, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Artemisia annua is known for its production of the antimalarial drug artemisinin (Graham et al, 2010;Tan et al, 2015;Xiao et al, 2016). Two kinds of trichomes are present on A. annua leaves: the glandular trichome where artemisinin is specifically synthesized; and the T-shaped nonglandular one (Duke & Paul, 1993;Tan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

HOMEODOMAIN PROTEIN 1 is required for jasmonate‐mediated glandular trichome initiation in Artemisia annua

et al. 2016

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Glandular trichomes are generally considered biofactories that produce valuable chemicals. Increasing glandular trichome density is a very suitable way to improve the productivity of these valuable metabolites, but little is known about the regulation of glandular trichome formation. Phytohormone jasmonate (JA) promotes glandular trichome initiation in various plants, but its mechanism is also unknown. By searching transcription factors regulated by JA in Artemisia annua, we identified a novel homeodomain-leucine zipper transcription factor, HOMEODOMAIN PROTEIN 1 (AaHD1), which positively controls both glandular and nonglandular trichome initiations. Overexpression of AaHD1 in A. annua significantly increased glandular trichome density without harming plant growth. Consequently, the artemisinin content was improved. AaHD1 interacts with A. annua jasmonate ZIM-domain 8 (AaJAZ8), which is a repressor of JA, thereby resulting in decreased transcriptional activity. AaHD1 knockdown lines show decreased sensitivity to JA on glandular trichome initiation, which indicates that AaHD1 plays an important role in JA-mediated glandular trichome initiation. We identified a new transcription factor that promotes A. annua glandular trichome initiation and revealed a novel molecular mechanism by which a homeodomain protein transduces JA signal to promote glandular trichome initiation. Our results also suggested a connection between glandular and nonglandular trichome formations.

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Section: The Committed Art Biosynthesis Pathwaymentioning

confidence: 99%

“…Indeed, the coordination of the ten cells that compose the peltate glandular trichome towards ART biosynthesis in artemisia is not fully understood (Xiao et al, 2016). Only the four sub-apical cells contain chloroplasts, and it appears that only the two apical secretory cells express the late enzymes of the ART pathway (Nguyen et al, 2011;Xiao et al, 2016). It would be valuable to have a better resolution of gene expression of each enzyme in specific cell types of the glandular structure, such as by using RNA in situ hybridization or confocal microscopy with a fluorescent protein fusion under native promoter.…”

Section: The Committed Art Biosynthesis Pathwaymentioning

confidence: 99%

MORPHOLOGICAL, GENETIC AND BIOCHEMICAL CHARACTERIZATION OF THE ANTI-MALARIAL HERB, Artemisia annua GERMPLASM COLLECTION AT WEST VIRGINIA UNIVERSITY

Samarasinghe¹

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Malaria is one of the deadliest diseases in human history. Nearly half of the world's population, is at the risk in 106 countries. Only in 2016, this disease killed about 445,000 people, 72% of them being children under age five. It also accounts for US $12 billion dollars of direct costs in Africa alone. Five different species of Plasmodium cause malaria but P. falciparum is the most detrimental one, causing 50% of all malaria cases and is considered as the deadliest parasite in humans. Artemisinin (ART), a 15 C sesquiterpenoid is currently the only precursor to the most effective anti-malarial drugs. The World Health Organization (WHO) recommends the use of ARTderived drugs in combination with other anti-malarial drugs (collectively called as Artemisininbased Combination Therapies, ACT), to prevent the development of ART resistance by the parasite. The natural source of ART is Artemisia annua, an Asteraceae plant native to East Asia. ART is synthesized in 10-cell glandular trichomes and accumulates extra-cellularly in the sub cuticular space. ART is synthesized in A. annua in low quantities, about 0.01-3% DW and, due to its complex molecular structure, it cannot be synthesized chemically in an economically viable way. Even though the semi-synthesis of ART has been successful in bioreactors, ART extraction from A. annua is much more economically viable. Therefore, it is important to understand the A. annua genetic contribution to ART synthesis to improve the ART yield of the plants. We characterized a collection of 12 different genotypes of Artemisia annua at West Virginia University in terms of developmental traits, biochemical profile, and gene expression to better understand the phenotypical differences of the germplasm in the collection. Plants were analyzed for height, biomass, leaf shape and leaf size, adaxial and abaxial trichome densities for morphological characterization. Freeze dried leaf material was extracted with hexane and an internal standard and the extractions were analyzed with GC-MS. Flash frozen leaf material were used to extract total RNA and analyzed for the gene expression of 15 genes with qRT-PCR. Based on the results, it was revealed that there is high phenotypical and metabolic variation among the genotypes. Monoterpenes made up for a large component of the hexane-extracted metabolome. Camphor and endo-borneol contributed significantly to differentiate the genotypes. Out of the all the genes analyzed, gene expression of three genes (FPS, CPR, and DBR2) were significantly different among the genotypes. Based on data, genotype J has the highest accumulation of ART and DHAA with anatomical characteristics supporting towards high ART and DHAA yield. Next, I and G genotypes also showed anatomical features supporting towards high ART and DHAA accumulation. The genotypes can be used to further investigate ideal genetic variations and allelic combinations for crop improvement in future.

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Artemisia annua glandular secretory trichomes: the biofactory of antimalarial agent artemisinin

Cited by 76 publications

References 75 publications

Overexpression of Artemisia annua Cinnamyl Alcohol Dehydrogenase Increases Lignin and Coumarin and Reduces Artemisinin and Other Sesquiterpenes

Overexpression of Artemisia annua Cinnamyl Alcohol Dehydrogenase Increases Lignin and Coumarin and Reduces Artemisinin and Other Sesquiterpenes

HOMEODOMAIN PROTEIN 1 is required for jasmonate‐mediated glandular trichome initiation in Artemisia annua

MORPHOLOGICAL, GENETIC AND BIOCHEMICAL CHARACTERIZATION OF THE ANTI-MALARIAL HERB, Artemisia annua GERMPLASM COLLECTION AT WEST VIRGINIA UNIVERSITY

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