Expression of β‐glucosidase increases trichome density and artemisinin content in transgenic Artemisia annua plants
Open accessAbstract
Summary: Artemisinin is highly effective against multidrug‐resistant strains of Plasmodium falciparum, the aetiological agent of the most severe form of malaria. However, a low level of accumulation of artemisinin in Artemisia annua is a major limitation for its production and delivery to malaria endemic areas of the world. While several strategies to enhance artemisinin have been extensively explored, enhancing storage capacity in trichome has not yet been considered. Therefore, trichome density was increased with the expression of β‐glucosidase (bgl 1) gene in A. annua through Agrobacterium‐mediated transformation. Transgene (bgl 1) integration and transcript were confirmed by molecular analysis. Trichome density increased up to 20% in leaves and 66% in flowers of BGL 1 transgenic plants than Artemisia control plants. High‐performance liquid chromatography, time of flight mass spectrometer data showed that artemisinin content increased up to 1.4% in leaf and 2.56% in flowers (per g DW), similar to the highest yields achieved so far through metabolic engineering. Artemisinin was enhanced up to five‐fold in BGL 1 transgenic flowers. This study opens the possibility of increasing artemisinin content by manipulating trichomes’ density, which is a major reservoir of artemisinin. Combining biosynthetic pathway engineering with enhancing trichome density may further increase artemisinin yield in A. annua. Because oral feeding of Artemisia plant cells reduced parasitemia more efficiently than the purified drug, reduced drug resistance and cost of prohibitively expensive purification process, enhanced expression should play a key role in making this valuable drug affordable to treat malaria in a large global population that disproportionally impacts low‐socioeconomic areas and underprivileged children.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Production of the antimalarial drug precursor artemisinic acid in engineered yeast
Ro, D.-K., Paradise, E. M., Ouellet, M., Fisher, K. J., Newman, K. L., Ndungu, J. M., Ho, K. A., Eachus, R. A., Ham, T. S., Kirby, J., et al. (2006) · Nature · doi:10.1038/nature04640 · Cited by 2,805 · see citing works
Qinghaosu (Artemisinin): an Antimalarial Drug from China
Klayman, D. L. (1985) · Science · doi:10.1126/science.3887571 · Cited by 2,186 · see citing works
Engineering a mevalonate pathway in Escherichia coli for production of terpenoids
Martin, V. J. J., Pitera, D. J., Withers, S. T., Newman, J. D., & Keasling, J. D. (2003) · Nature Biotechnology · doi:10.1038/nbt833 · Cited by 1,720 · see citing works
Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis
Flint, H. J., Bayer, E. A., Rincón, M. T., Lamed, R., & White, B. A. (2008) · Nature Reviews Microbiology · doi:10.1038/nrmicro1817 · Cited by 1,710 · see citing works
PLANT HORMONES: Biosynthesis, Signal Transduction, Action
Davies, P. J. (2010) · doi:10.1007/978-1-4020-2686-7 · Cited by 1,139 · see citing works
Recognition and Degradation of Plant Cell Wall Polysaccharides by Two Human Gut Symbionts
Martens, E. C., Lowe, E. C., Chiang, H. C., Pudlo, N. A., Wu, M., McNulty, N. P., Abbott, D. W., Henrissat, B., Gilbert, H. J., Bolam, D. N., et al. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001221 · Cited by 847 · see citing works
The anti-malarial artesunate is also active against cancer
Efferth, T., Dunstan, H. M., Sauerbrey, A., Miyachi, H., & Chitambar, C. R. (2001) · International Journal of Oncology · doi:10.3892/ijo.18.4.767 · Cited by 567 · see citing works
Graham, I. A., Besser, K., Blumer, S., Branigan, C. A., Czechowski, T., Elias, L., Guterman, I., Harvey, D., Isaac, P. G., Khan, A. M., et al. (2010) · Science · doi:10.1126/science.1182612 · Cited by 348 · see citing works
Wallaart, T. E., Pras*, N., Beekman, A., & Quax, W. J. (2000) · Planta Medica · doi:10.1055/s-2000-11115 · Cited by 281 · cited 1× · see citing works
“Large differences in artemisinin content have been reported, depending on genotype (variety), season (environmental changes), cultivation condition (soil nature) and plant developmental stage (Ferreira et al., 1995; Wallaart et al., 2000; Delabays et al., 2001; Yang et al., 2009).”
Backgroundde Vries, P. J., & Dien, T. K. (1996) · Drugs · doi:10.2165/00003495-199652060-00004 · Cited by 277 · see citing works
Development and Fine Structure of the Glandular Trichomes of Artemisia annua L.
Duke, S. O., & Paul, R. N. (1993) · International Journal of Plant Sciences · doi:10.1086/297096 · Cited by 276 · see citing works
Duke, M. V., Paul, R. N., Elsohly, H. N., Sturtz, G., & Duke, S. O. (1994) · International Journal of Plant Sciences · doi:10.1086/297173 · Cited by 252 · see citing works
Artemisinin, a Novel Antimalarial Drug: Biochemical and Molecular Approaches for Enhanced Production
Abdin, M. Z., Israr, M., Rehman, R. U., & Jain, S. K. (2003) · Planta Medica · doi:10.1055/s-2003-38871 · Cited by 252 · see citing works
Avery, M. A., Chong, W. K. M., & Jennings-White, C. (1992) · Journal of the American Chemical Society · doi:10.1021/ja00029a028 · Cited by 250 · cited 2× · see citing works
“Although organic synthesis of artemisinin is possible, its low yield makes it economically nonviable as a mean of drug production (Avery et al. 1992).”
BackgroundThe Mechanism of Enzymatic Cellulose Degradation
BERGHEM, L. E. R., & Pettersson, L. G. (1974) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1974.tb03621.x · Cited by 249 · see citing works
Taiz, L. (1992) · Journal of Experimental Biology · doi:10.1242/jeb.172.1.113 · Cited by 245 · see citing works
Olsson, M. E., Olofsson, L. M., Lindahl, A.-L., Lundgren, A., Brodelius, M., & Brodelius, P. E. (2009) · Phytochemistry · doi:10.1016/j.phytochem.2009.07.009 · Cited by 241 · see citing works
Maes, L., Van Nieuwerburgh, F. C. W., Zhang, Y., Reed, D. W., Pollier, J., Vande Casteele, S. R. F., Inzé, D., Covello, P. S., Deforce, D. L. D., & Goossens, A. (2011) · New Phytologist · doi:10.1111/j.1469-8137.2010.03466.x · Cited by 240 · see citing works
Romero, M. R., Efferth, T., Serrano, M. A., Castaño, B., Macı́as, R. I. R., Briz, Ó., & Marı́n, J. J. G. (2005) · Antiviral Research · doi:10.1016/j.antiviral.2005.07.005 · Cited by 233 · see citing works
Chen, D.-H., Ye, H.-C., & Li, G.-F. (2000) · Plant Science · doi:10.1016/s0168-9452(00)00217-x · Cited by 225 · see citing works
Lakshmi, P. S., Verma, D., Yang, X., Lloyd, B., & Daniell, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054708 · Cited by 200 · see citing works
Self-citationDelabays, N., Simonnet, X., & Gaudin, M. (2001) · Current Medicinal Chemistry · doi:10.2174/0929867013371635 · Cited by 178 · cited 1× · see citing works
“Large differences in artemisinin content have been reported, depending on genotype (variety), season (environmental changes), cultivation condition (soil nature) and plant developmental stage (Ferreira et al., 1995; Wallaart et al., 2000; Delabays et al., 2001; Yang et al., 2009).”
BackgroundTan, H., Ling Zhi, X. I. A. O., Gao, S., Li, Q., Chen, J., Xiao, Y., Ji, Q., Chen, R., Chen, W., & Zhang, L. (2015) · Molecular Plant · doi:10.1016/j.molp.2015.04.002 · Cited by 178 · see citing works
Davoodi‐Semiromi, A., Schreiber, M., Nalapalli, S., et al. (2009) · Plant Biotechnology Journal · doi:10.1111/j.1467-7652.2009.00479.x · Cited by 175 · see citing works
Kwon, K., Verma, D., Singh, N. D., Herzog, R. W., & Daniell, H. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.10.005 · Cited by 150 · see citing works
Self-citationFloral Morphology of Artemisia annua with Special Reference to Trichomes
Janick, J. (1995) · International Journal of Plant Sciences · doi:10.1086/297304 · Cited by 129 · see citing works
Dried Whole Plant Artemisia annua as an Antimalarial Therapy
Elfawal, M. A., Towler, M. J., Reich, N. G., Golenbock, D. T., Weathers, P. J., & Rich, S. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052746 · Cited by 128 · see citing works
Ferreira, J., Simon, J., & Janick, J. (1995) · Planta Medica · doi:10.1055/s-2006-958040 · Cited by 128 · cited 3× · see citing works
“Some researchers believe that the artemisinin content reaches its peak before flowering (Abdin et al., 2003; Mauji Ram et al., 2010), while others have indicated the peak occurs at the full-flowering stage (Ferreira et al., 1995a).”
BackgroundCovello, P. S. (2008) · Phytochemistry · doi:10.1016/j.phytochem.2008.10.001 · Cited by 127 · cited 2× · see citing works
“Artemisinin is a sesquiterpenoid, produced in glandular trichomes of Artemisia annua (Covello 2008).”
BackgroundElfawal, M. A., Towler, M. J., Reich, N. G., Weathers, P. J., & Rich, S. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1413127112 · Cited by 124 · see citing works
Romero, M. R., Serrano, M. A., Vallejo, M., Efferth, T., Alvarez, M., & Marı́n, J. J. G. (2006) · Planta Medica · doi:10.1055/s-2006-947198 · Cited by 122 · see citing works
Lommen, W. J., Schenk, E., Bouwmeester, H. J., & Verstappen, F. W. (2006) · Planta Medica · doi:10.1055/s-2005-916202 · Cited by 119 · see citing works
Jones, R. M., Chichester, J. A., Mett, V. L., Jaje, J., Tottey, S., Manceva, S. D., Casta, L. J., Gibbs, S. K., Musiychuk, K., Shamloul, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079538 · Cited by 117 · see citing works
Jin, S., Kanagaraj, A., Verma, D., et al. (2010) · PLANT PHYSIOLOGY · doi:10.1104/pp.110.160754 · Cited by 117 · see citing works
Sembdner, G., Atzorn, R., & Schneider, G. (1994) · Plant Molecular Biology · doi:10.1007/bf00016485 · Cited by 110 · see citing works
Differential transcriptome analysis of glandular and filamentous trichomes in Artemisia annua
Soetaert, S. S., Van Neste, C. M., Vandewoestyne, M. L., Head, S. R., Goossens, A., Van Nieuwerburgh, F. C., & Deforce, D. L. (2013) · BMC Plant Biology · doi:10.1186/1471-2229-13-220 · Cited by 109 · see citing works
Kwon, K., Nityanandam, R., New, J. S., & Daniell, H. (2012) · Plant Biotechnology Journal · doi:10.1111/pbi.12008 · Cited by 98 · see citing works
Self-citationSherman, A., Su, J., Lin, S., Wang, X., Herzog, R. W., & Daniell, H. (2014) · Blood · doi:10.1182/blood-2013-10-528737 · Cited by 94 · see citing works
Self-citationLimaye, A., Koya, V., Samsam, M., et al. (2006) · The FASEB Journal · doi:10.1096/fj.05-5134fje · Cited by 94 · see citing works
The safety of artemisinins during pregnancy: a pressing question
Dellicour, S., Hall, S. T., Chandramohan, D., & Greenwood, B. M. (2007) · Malaria Journal · doi:10.1186/1475-2875-6-15 · Cited by 92 · see citing works
Charles, D. J., Simon, J. E., Wood, K. V., & Heinstein, P. F. (1990) · Journal of Natural Products · doi:10.1021/np50067a021 · Cited by 87 · see citing works
Arsenault, P. R., Vail, D. R., Wobbe, K. K., Erickson, K., & Weathers, P. J. (2010) · PLANT PHYSIOLOGY · doi:10.1104/pp.110.162552 · Cited by 85 · see citing works
State of the art of the production of the antimalarial compound artemisinin in plants
Geldre, E. V., Vergauwe, A., & den Eeckhout, E. V. (1997) · Plant Molecular Biology · doi:10.1023/a:1005716600612 · Cited by 84 · see citing works
Shil, P. K., Kwon, K., Zhu, P., Verma, A., Daniell, H., & Li, Q. (2014) · Molecular Therapy · doi:10.1038/mt.2014.179 · Cited by 81 · see citing works
Self-citationOral Delivery of Bioencapsulated Proteins Across Blood–Brain and Blood–Retinal Barriers
Kohli, N., Westerveld, D., Ayache, A., Verma, A., Shil, P. K., Prasad, T., Zhu, P., Chan, S. L., Li, Q., & Daniell, H. (2013) · Molecular Therapy · doi:10.1038/mt.2013.273 · Cited by 78 · see citing works
Self-citationNieuwerburgh, F. V., Casteele, S. V., Maes, L., Goossens, A., Inzé, D., Bocxlaer, J. V., & Deforce, D. L. D. (2006) · Journal of Chromatography A · doi:10.1016/j.chroma.2006.03.121 · Cited by 73 · see citing works
Vergauwe, A., Cammaert, R., Vandenberghe, D., Genetello, C., Inzé, D., Montagu, M. V., & den Eeckhout, E. V. (1996) · Plant Cell Reports · doi:10.1007/bf00231590 · Cited by 72 · see citing works
Davies, M. J., Atkinson, C. J., Burns, C., Woolley, J. G., Hipps, N. A., Arroo, R., Dungey, N., Robinson, T., Brown, P., Flockart, I., et al. (2009) · Annals of Botany · doi:10.1093/aob/mcp126 · Cited by 71 · see citing works
Potential Ecological Roles of Artemisinin Produced by Artemisia annua L.
Knudsmark Jessing, K., Duke, S. O., & Cedergreeen, N. (2014) · Journal of Chemical Ecology · doi:10.1007/s10886-014-0384-6 · Cited by 69 · see citing works
Han, J., Wang, H., Ye, H., Liu, Y., Li, Z., Zhang, Y., Zhang, Y., Fang, Y., & Li, G. (2004) · Plant Science · doi:10.1016/j.plantsci.2004.07.020 · Cited by 67 · see citing works
Gibberellin conjugates: an overview
Schneider, G., & Schliemann, W. (1994) · Plant Growth Regulation · doi:10.1007/bf00029898 · Cited by 66 · see citing works
HMG-CoA reductase limits artemisinin biosynthesis and accumulation in Artemisia annua L. plants
Ram, M., Khan, M. A., Jha, P., Khan, S., Kiran, U., Ahmad, M. M., Javed, S., & Abdin, M. Z. (2010) · Acta Physiologiae Plantarum · doi:10.1007/s11738-010-0470-5 · Cited by 59 · see citing works
Lu, X., Shen, Q., Zhang, L., Zhang, F., Jiang, W., Lv, Z., Yan, T., Fu, X., Wang, G., & Tang, K. (2013) · Industrial Crops and Products · doi:10.1016/j.indcrop.2013.04.045 · Cited by 53 · see citing works
Ferreira, J., Simon, J. E., & Janick, J. (1995) · Planta Medica · doi:10.1055/s-2006-958098 · Cited by 53 · see citing works
Isolation of high artemisinin-yielding clones of Artemisia annua
Jain, D. C., Mathur, A. K., Gupta, M. M., Singh, A. K., Verma, R. K., Gupta, A. P., & Kumar, S. (1996) · Phytochemistry · doi:10.1016/s0031-9422(96)00369-x · Cited by 51 · see citing works
Self-citationKjær, A., Grevsen, K., & Jensen, M. (2012) · AoB Plants · doi:10.1093/aobpla/pls018 · Cited by 45 · see citing works
(2007) · AFRICAN JOURNAL OF BIOTECHNOLOGY · doi:10.5897/ajb2007.000-2198 · Cited by 43 · see citing works
Yang, R.-Y., Zeng, X.-M., Lu, Y.-Y., Lu, W.-J., Feng, L.-L., Yang, X.-Q., & Zeng, Q.-P. (2010) · Planta Medica · doi:10.1055/s-0029-1240620 · Cited by 40 · see citing works
Understanding artemisinin resistance
Sibley, C. H. (2015) · Science · doi:10.1126/science.aaa4102 · Cited by 34 · see citing works
SEASONAL ACCUMULATION OF ARTEMISININ IN ARTEMISIA ANNUA L.
Morales, M. R., Charles, D. J., & Simon, J. E. (1993) · Acta Horticulturae · doi:10.17660/actahortic.1993.344.48 · Cited by 33 · see citing works
Selection of hairy root clones of Artemisia annua L. for artemisinin production
Xie, D., Ye, H., Li, G., Guo, Z., ZOU, Z., & Guo, Z. (2001) · Israel Journal of Plant Sciences · doi:10.1560/n11n-6blg-er7c-xkct · Cited by 29 · see citing works
Laughlin, J. C. (1995) · Acta Horticulturae · doi:10.17660/actahortic.1995.390.8 · Cited by 28 · see citing works
Loss of artemisinin produced by Artemisia annua L. to the soil environment
Jessing, K. K., Nina Cedergreen, G., Mayer, P., Libous-Bailey, L., Strobel, B. W., Rimando, A. M., & Duke, S. O. (2012) · Industrial Crops and Products · doi:10.1016/j.indcrop.2012.06.033 · Cited by 27 · see citing works
EFFECT OF AGRONOMIC PRACTICES ON PLANT YIELD AND ANTI-MALARIAL CONSTITUENTS OF ARTEMISIA ANNUA L.
Laughlin, J. C. (1993) · Acta Horticulturae · doi:10.17660/actahortic.1993.331.8 · Cited by 21 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Dellicour S Hall S Chandramohan D Greenwood BD The safety of artemisinins during pregnancy: a pressing question. Malar. J 2007 6 15 17300719 PMC1802871
- Duke SO Glandular trichomes - a focal point of chemical and structural interactions. International Journal of Plant Sciences 1994 155 617 620
Cited by
Sorted by citations
Cannabis sativa: The Plant of the Thousand and One Molecules
Andre, C. M., Hausman, J.-F., & Guerriero, G. (2016) · Frontiers in Plant Science · doi:10.3389/fpls.2016.00019 · Cited by 1,544 · see citing works
“An additional study on A. annua has shown that the expression of a β-glucosidase from Trichoderma reesei increases glandular trichome density and artemisinin production (Singh et al., 2015).”
BackgroundWani, K. I., Choudhary, S., Zehra, A., Naeem, M., Weathers, P., & Aftab, T. (2021) · Planta · doi:10.1007/s00425-021-03676-3 · Cited by 74 · see citing works
Qin, W., Xie, L., Li, Y., Liu, H., Fu, X., Chen, T., Hassani, D., Li, L., Sun, X., & Tang, K. (2021) · Frontiers in Plant Science · doi:10.3389/fpls.2021.657156 · Cited by 66 · see citing works
- Authors
- Singh, N. D., Kumar, S., & Daniell, H.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Daniell, Henry
- Venue
- Plant Biotechnology Journal
- Publisher
- Wiley
- Published
- 2015-09-11
- Volume
- 14
- Issue
- 3
- Pages
- 1034-1045
- ISSN
- 1467-7644 (ISSN-L)
- 1467-7652
- PMC
- PMC4767539
- OpenAlex
- W2123530556
- Cited by
- 67
- References
- 64
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 12 · 2022: 12 · 2021: 10 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 6 · 2015: 2
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Plant Biotechnology Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 GM 63879, R01 HL 109442, R01 HL 107904)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant tissue culture and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Transgenic Plants and Applications
- Keywords
- β-glucosidase, trichome density, artemisinin biosynthesis, Artemisia annua, transgenic plants, metabolic engineering, Plasmodium falciparum, oral drug delivery, Agrobacterium-mediated transformation
- MeSH terms
- beta-Glucosidase, Chromatography, High Pressure Liquid, Transformation, Genetic, Plant Leaves, Gene Dosage, Transgenes, Plants, Genetically Modified, Artemisia annua, Artemisinins, Trichomes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review