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Information on EC 1.3.1.92 - artemisinic aldehyde DELTA11(13)-reductase
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1.3.1.92 artemisinic aldehyde DELTA11(13)-reductaseIUBMB Comments
Cloned from Artemisia annua. In addition to the reduction of artemisinic aldehyde it is also able to a lesser extent to reduce artemisinic alcohol and artemisinic acid. Part of the biosyntheis of artemisinin.
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Word Map
- 1.3.1.92
- artemisinin
-
artemisia
- annua
- trichomes
- cyp71av1
- glandular
- amorpha-4,11-diene
-
trichome-specific
- hydroxylase
-
antimalarial
-
malaria
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dihydroartemisinic
- synthesis
- medicine
- drug development
The expected taxonomic range for this enzyme is: Artemisia annua
Reaction Schemes
Synonyms
artemisinic aldehyde DELTA11(13) double-bond reductase, artemisinic aldehyde DELTA11(13) reductase, Dbr2, double bond reductase 2, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Dbr2
Dbr2
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-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(11R)-dihydroartemisinic aldehyde + NADP+ = artemisinic aldehyde + NADPH + H+
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
artemisinic aldehyde:NADP+ oxidoreductase
Cloned from Artemisia annua. In addition to the reduction of artemisinic aldehyde it is also able to a lesser extent to reduce artemisinic alcohol and artemisinic acid. Part of the biosyntheis of artemisinin.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(+)-carvone + NADH + H+
(1R,4S)-isodihydrocarvone + NAD+
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plus about 20% of (1S,4S)-dihydrocarvone
-
?
2E-nonenal + NADH + H+
nonanal + NAD+
about 12% of the activity with artemisinic aldehyde
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-
?
artemisinic aldehyde + NADH + H+
(11R)-dihydroartemisinic aldehyde + NAD+
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-
-
?
artemisinic aldehyde + NADPH + H+
dihydroartemisinic aldehyde + NADP+
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-
-
?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
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-
-
-
?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
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-
-
?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
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-
-
-
?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
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-
-
?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
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double bond reductase 2 (DBR2) reduces the DELTA11(13) double bond of artemisinic aldehyde
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-
?
additional information
?
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no substrate: arteannuin B, artemisinic acid, artemisinic alcohol, artemisitene, coniferyl aldehyde, (2E)-nonenal, alpha-pinene, (+)-pulegone, and sabinone
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additional information
?
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no substrate: arteannuin B, artemisinic acid, artemisinic alcohol, artemisitene, coniferyl aldehyde, (2E)-nonenal, alpha-pinene, (+)-pulegone, and sabinone
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additional information
?
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GC-MS analysis of dihydroartemisinic acid synthesized in different plant varieties, overview
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additional information
?
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LC-MS/MS analysis of dihydroartemisinic acid synthesized in plants
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additional information
?
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the conversion of dihydroartemisinic acid to artemisinin is a non-enzymatic photochemical oxidation process
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
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?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
C5H429
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-
?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
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-
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-
?
artemisinic aldehyde + NADPH + H+
(11R)-dihydroartemisinic aldehyde + NADP+
C5H429
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?
additional information
?
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C5H429
GC-MS analysis of dihydroartemisinic acid synthesized in different plant varieties, overview
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additional information
?
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LC-MS/MS analysis of dihydroartemisinic acid synthesized in plants
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
miconazole
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0.2 mM miconazole induce a 2.5-fold increase of artemisinin production after 24 h, but have severe effects on cell viability
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
brenda
cvs. 2/39, Chongqing, and Anamed with high artemisin production, and cvs. Meise, Iran#8, Iran#14, Iran#24, and Iran#47 with low artemisin production
UniProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
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presence of a number of biosynthetic enzymes such as the amorpha-4,11-diene synthase and the amorpha-4,11-diene hydroxylase as well as artemisinic alcohol and dihydroartemisinic aldehyde dehydrogenase activities in both leaves and glandular trichomes
brenda
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glandular trichome, presence of a number of biosynthetic enzymes such as the amorpha-4,11-diene synthase and the amorpha-4,11-diene hydroxylase as well as artemisinic alcohol and dihydroartemisinic aldehyde dehydrogenase activities in both leaves and glandular trichomes
brenda
additional information
artemisinin is mainly produced and stored in the glandular secretory trichomes on leaves, stems, and inflorescences
brenda
additional information
enzyme expression levels in different plant varieties, overview
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
physiological function
metabolism
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artemisinic aldehyde 11 (13) reductase (DBR2) is the checkpoint enzyme catalyzing artemisinic aldehyde to form dihydroartemisinic aldehyde directly involved in artemisinin biosynthetic pathway
metabolism
the final step of artemisin biosynthesis involves two genes, a double bond reductase (DBR2) and an aldehyde dehydrogenase (ALDH1)
physiological function
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the early steps in artemisinin biosynthesis involve amorpha-4,11-diene hydroxylation to artemisinic alcohol, followed by oxidation to artemisinic aldehyde, reduction of the C11-C13 double bond to dihydroartemisinic aldehyde and oxidation to dihydroartemisinic acid
physiological function
the enzyme plays an important role in the biosynthesis of the antimalarial artemisinin in Artemisia annua. The high artemisin producing plant varieties 2/39, Chongqing, and Anamed produce more artemisinin than arteannuin B, while the low artemisin producing plant varieties Meise, Iran#8, Iran#14, Iran#24, and Iran#47 produce more arteannuin B than artemisinin
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
Sequence
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
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heterologous expression of Artemisia annua amorphadiene synthase and CYP71AV1, the cytochrome P450 responsible for oxidation of amorphadiene, in tobacco lead to the accumulation of amorphadiene and artemisinic alcohol, but not artemisinic acid, in leaf. Additional expression of artemisinic aldehyde DELTA11(13) double-bond reductase with or without aldehyde dehydrogenase 1 leads to the additional accumulation dihydroartemisinic alcohol
additional information
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the yield of artemisinin from Artemisia annua is relatively low when cultivated under Indian climatic conditions. Artemisinin biosynthesized at clinically meaningful levels in Nicotiana tabacum by engineering two metabolic pathways targeted to three different cellular compartments (chloroplast, nucleus, and mitochondria). The doubly transgenic lines show a 3fold enhancement of isopentenyl diphosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts results in higher expression and an efficient photooxidation of dihydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic Nicotiana tabacum plants inhibit in vitro growth progression of Plasmodium falciparum-infected red blood cells, parasitemia is observed in mice fed with pure artemisinin as well as those fed with the wild-type plant extract, Plasmodium berghei murine malaria model. Artemisinin biosynthesis by sequential metabolic engineering of chloroplast and nuclear genomes, overview
additional information
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branch pathway blocking in Artemisia annua is a useful method for obtaining high yield artemisinin. In anti-squalene synthase (SQS) transgenic plants, the transcription levels of beta-caryophyllene synthase (CPS), beta-farnesene synthase (BFS), germacrene A synthase (GAS), amorpha-4,11-diene synthase (ADS), amorphadiene 12-hydroxylase (CYP71AV1) and aldehyde dehydrogenase 1 (ALDH1) all increase. Contents of artemisinin and dihydroartemisinic acid are enhanced by 71% and 223%, respectively, while beta-farnesene is raised to 123% compared to control. The mRNA level of artemisinic aldehyde DELTA11(13) reductase (DBR2) does negligibly change in almost all transgenic plants, overview
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PURIFICATION/commentary
ORGANISM
UNIPROT
LITERATURE
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CLONED/commentary
ORGANISM
UNIPROT
LITERATURE
gene DBR2, cloning, sequencing, and analysis of the promoter of the DBR2 gene, detailed overview. The activity of the artemisinic aldehyde DELTA11(13) reductase promoter is important for artemisinin yield in different chemotypes of Artemisia annua, quantitative real-time PCR expression analysis, overview
gene DBR2, overexpression in Artemisia annua under control of the CaMV 35S promoter via transfecton through Agrobacterium tumefaciens strain LBA4404 mediated leaf disc transformation, quantitative real-time PCR expression analysis, method evaluation
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gene DBR2, recombinant expression of the enzyme in transgenic Nicotiana tabacum plant leaf chloroplasts via transfection with Agrobacterium tumefaciens strain EHA105, nuclear genome transformation of homoplastomic plant
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
expression levels of farnesyl diphosphate synthase (FPS), cytochrome P450-dependent hydroxylase CYP71AV1, and double bond reductase 2 (DBR2) are increased significantly in plants overexpressing Artemisia annua allene oxide cyclase, AaAOC. The product of AOC is jasmonate, that induces the expression of FPS, CYP71AV1, and DBR2
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methyljasmonate does not induce significant changes in the expression of DBR2
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the enzyme DBR2 is induced by 0.12 mmol/l of cadmium. Appropriate doses of cadmium can increase the concentrations of artemisinic metabolites at a certain time point by upregulating the relative expression levels of key enzyme genes involved in artemisinin biosynthesis, overview
three jasmonate-responsive transcription factors, ethylene response factor 1, ethylene response factor 2, and octadecanoidresponsive AP2/ERF, all transcriptionally activate the expression of artemisinin biosynthetic genes, such as amorpha-4,11-diene synthase (ADS), CYP71AV1, DBR2, and aldehyde dehydrogenase 1 (ALDH1). Cold stress indirectly activates the DBR2 expression by increasing the amount of jasmonate through upregulation of jasmonate biosynthetic genes (LOX1, LOX2, allene oxide cyclase [AOC], and jasmonate resistant 1 [JAR1]). Levels of artemisinin and related secondary metabolites, such as dihydroartemisinic acid, artemisinin B, and artemisinic acid, are increased in Artemisia annua under cold stress
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treatment for 30 min and 4 h with miconazole induces about four- und fivefold upregulation of the DBR2 gene, respectively
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
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oral feeding of whole intact plant cells bioencapsulating the artemisinin reduces the Plasmodium falciparum parasitemia levels in challenged mice in comparison with commercial drug. The synergistic approache may facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants
medicine
artemisinin is the main ingredient for malaria prevention. The World Health Organization recommends artemisinin combination therapies (ACT) as the first-line therapy for malaria worldwide
synthesis
synthesis
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production of artemisin by incubating a mixture of artemisin precursors from engineered Saccharomyces cerevisiae with a cell-free extract of Artemisia annua. Use of cold-acclimated Artemisia annua cell-free extract gives rise to considerable artemisin content up to 0.65%
synthesis
for enhanced artemisin production, Appropriate doses of Cd can increase the concentrations of artemisinic metabolites at a certain time point by upregulating the relative expression levels of key enzyme genes involved in artemisinin biosynthesis
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Zeng, Q.; Zeng, L.; Lu, W.; Feng, L.; Yang, R.; Qiu, F.
Enhanced artemisinin production from engineered yeast precursors upon biotransformation
Biocatal. Biotransform.
30
190-202
2012
Artemisia annua
-
brenda
Zhang, Y.; Teoh, K.H.; Reed, D.W.; Maes, L.; Goossens, A.; Olson, D.J.; Ross, A.R.; Covello, P.S.
The molecular cloning of artemisinic aldehyde DELTA11(13) reductase and its role in glandular trichome-dependent biosynthesis of artemisinin in Artemisia annua
J. Biol. Chem.
283
21501-21508
2008
Artemisia annua, Artemisia annua (C5H429)
brenda
Caretto, S.; Quarta, A.; Durante, M.; Nisi, R.; De Paolis, A.; Blando, F.; Mita, G.
Methyl jasmonate and miconazole differently affect arteminisin production and gene expression in Artemisia annua suspension cultures
Plant Biol.
13
51-58
2011
Artemisia annua (C5H429)
brenda
Zhang, Y.; Nowak, G.; Reed, D.W.; Covello, P.S.
The production of artemisinin precursors in tobacco
Plant Biotechnol. J.
9
445-454
2011
Artemisia annua, Artemisia annua (C5H429)
brenda
Bertea, C.; Freije, J.; Van Der Woude, H.; Verstappen, F.; Perk, L.; Marquez, V.; De Kraker, J.; Posthumus, M.; Jansen, B.; De Groot, A.; Franssen, M.; Bouwmeester, H.
Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua
Planta Med.
71
40-47
2005
Artemisia annua
brenda
Yuan, Y.; Liu, W.; Zhang, Q.; Xiang, L.; Liu, X.; Chen, M.; Lin, Z.; Wang, Q.; Liao, Z.
Overexpression of artemisinic aldehyde DELTA11(13) reductase gene - enhanced artemisinin and its relative metabolite biosynthesis in transgenic Artemisia annua L
Biotechnol. Appl. Biochem.
62
17-23
2015
Artemisia annua (C5H429)
brenda
Liu, W.; Wang, H.; Chen, Y.; Zhu, S.; Chen, M.; Lan, X.; Chen, G.; Liao, Z.
Cold stress improves the production of artemisinin depending on the increase in endogenous jasmonate
Biotechnol. Appl. Biochem.
64
305-314
2016
Artemisia annua (C5H429)
brenda
Zhou, L.; Yang, G.; Sun, H.; Tang, J.; Yang, J.; Wang, Y.; Garran, T.A.; Guo, L.
Effects of different doses of cadmium on secondary metabolites and gene expression in Artemisia annua L
Front. Med.
11
137-146
2017
Artemisia annua (C5H429)
brenda
Malhotra, K.; Subramaniyan, M.; Rawat, K.; Kalamuddin, M.; Qureshi, M.I.; Malhotra, P.; Mohmmed, A.; Cornish, K.; Daniell, H.; Kumar, S.
Compartmentalized metabolic engineering for artemisinin biosynthesis and effective malaria treatment by oral delivery of plant cells
Mol. Plant
9
1464-1477
2016
Artemisia annua (C5H429)
brenda
Lv, Z.; Zhang, F.; Pan, Q.; Fu, X.; Jiang, W.; Shen, Q.; Yan, T.; Shi, P.; Lu, X.; Sun, X.; Tang, K.
Branch pathway blocking in Artemisia annua is a useful method for obtaining high yield artemisinin
Plant Cell Physiol.
57
588-602
2016
Artemisia annua (C5H429)
brenda
Yang, K.; Monfared, S.R.; Monafared, R.S.; Wang, H.; Lundgren, A.; Brodelius, P.E.
The activity of the artemisinic aldehyde ?11(13) reductase promoter is important for artemisinin yield in different chemotypes of Artemisia annua L.
Plant Mol. Biol.
88
325-340
2015
Artemisia annua (C5H429)
brenda
Lu, X.; Zhang, F.; Shen, Q.; Jiang, W.; Pan, Q.; Lv, Z.; Yan, T.; Fu, X.; Wang, Y.; Qian, H.; Tang, K.
Overexpression of allene oxide cyclase improves the biosynthesis of artemisinin in Artemisia annua L.
PLoS ONE
9
e91741
2014
Artemisia annua (C5H429)
brenda
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