Relative expression of genes of terpene metabolism in different tissues of Artemisia annuaL
Open accessAbstract
Background: Recently, Artemisia annua L. (annual or sweet wormwood) has received increasing attention due to the fact that the plant produces the sesquiterpenoid endoperoxide artemisinin, which today is widely used for treatment of malaria. The plant produces relatively small amounts of artemisinin and a worldwide shortage of the drug has led to intense research in order to increase the yield of artemisinin. In order to improve our understanding of terpene metabolism in the plant and to evaluate the competition for precursors, which may influence the yield of artemisinin, we have used qPCR to estimate the expression of 14 genes of terpene metabolism in different tissues. Results: The four genes of the artemisinin biosynthetic pathway (amorpha-4,11-diene synthase, amorphadiene-12-hydroxylase, artemisinic aldehyde ∆11(13) reductase and aldehyde dehydrogenase 1) showed remarkably higher expression (between ~40- to ~500-fold) in flower buds and young leaves compared to other tissues (old leaves, stems, roots, hairy root cultures). Further, dihydroartemisinic aldehyde reductase showed a very high expression only in hairy root cultures. Germacrene A and caryophyllene synthase were mostly expressed in young leaves and flower buds while epi-cedrol synthase was highly expressed in old leaves. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase exhibited lower expression in old leaves compared to other tissues. Farnesyldiphosphate synthase, squalene synthase, and 1-deoxy-D-xylulose-5-phosphate reductoisomerase showed only modest variation in expression in the different tissues, while expression of 1-deoxy-D-xylulose-5-phosphate synthase was 7-8-fold higher in flower buds and young leaves compared to old leaves. Conclusions: Four genes of artemisinin biosynthesis were highly expressed in flower buds and young leaves (tissues showing a high density of glandular trichomes). The expression of dihydroartemisinic aldehyde reductase has been suggested to have a negative effect on artemisinin production through reduction of dihydroartemisinic aldehyde to dihydroartemisinic alcohol. However, our results show that this enzyme is expressed only at low levels in tissues producing artemisinin and consequently its effect on artemisinin production may be limited. Finally, squalene synthase but not other sesquiterpene synthases appears to be a significant competitor for farnesyl diphosphate in artemisinin-producing tissues.
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TL;DR
qPCR profiling of 14 terpene-metabolism genes across *Artemisia annua* tissues showed that four artemisinin biosynthetic genes (ADS, CYP71AV1, DBR2, ALDH1) are highly expressed in flower buds and young leaves. The authors conclude that squalene synthase may compete significantly for farnesyl diphosphate in artemisinin-producing tissues, whereas RED1 is unlikely to limit artemisinin production.
Key findings
- The four artemisinin pathway genes showed ~40- to ~500-fold higher expression in flower buds and young leaves than in old leaves, stems, roots, and hairy roots: ADS ~500- and ~150-fold, CYP71AV1 ~150- and ~150-fold, DBR2 ~40- and ~70-fold, and ALDH1 ~250- and ~130-fold in flower buds and young leaves, respectively.
- RED1 was highly expressed in hairy roots (~50-fold more than old leaves) but low in flower buds, young leaves, and stems; the authors conclude RED1 likely has limited influence on artemisinin production because of low expression in artemisinin-producing tissues, high Km for dihydroartemisinic aldehyde, and low relative turnover potential.
- DXS expression was 7–8-fold higher in flower buds and young leaves than in old leaves; HDR was 10–30-fold higher in old leaves than in other tissues; HMGR was ~20- and ~8-fold higher in flower buds and young leaves than in old leaves; FDS, SQS, and DXR varied only modestly.
- ADS dominated sesquiterpene synthase expression in flower buds and young leaves (normalized transcript amounts 8780 and 6654 vs. GAS in stems = 1), while ECS was highly expressed in old leaves (43000); assuming SQS kcat ~1 s−1, SQS had about 45- and 25-fold higher FDP turnover potential than ADS in flower buds and young leaves.
Methods
- *Artemisia annua* L. cv Artemis plants were grown under 16 h days/8 h nights, then flower buds were induced by 21 days of short-day treatment (8 h day); flower buds, young leaves, old leaves, stems, roots, and hairy root cultures were collected from 5–6-month-old plants.
- RNA was extracted, reverse transcribed, and analyzed by qPCR with 18 primer pairs for 14 terpene-metabolism transcripts plus reference genes; primer efficiencies ranged from 1.82 to 1.93, and CPR, β-actin, and PAL were selected as reference genes using BestKeeper.
- Relative expression was calculated with REST 2009 and the 2^-ΔΔCT method; fluorescence microscopy was used to compare trichome densities, with young leaves estimated at ~300±40 trichomes/cm² and old leaves at 130±25 trichomes/cm².
Limitations
- The paper states that no kcat value is available for CYP71AV1, so it was excluded from the relative turnover estimation; it also states that no information is available on intracellular transport of artemisinin pathway intermediates, and that expression data in Table 3 come from different studies and varieties and are not directly comparable.
- Evident from the text: the study measures transcript levels by qPCR, not enzyme protein abundance or activity; the turnover-potential estimates assume transcription is proportional to active sites, enzymes work at substrate saturation, and the NADPH/NADP+ ratio is optimal.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 46 cited sources checked · 0 supported · 0 flagged
- Findingown data
HMGR exhibited lower expression in old leaves compared to other tissues.
“3-Hydroxy-3-methyl-glutaryl coenzyme A reductase exhibited lower expression in old leaves compared to other tissues.”
Quote in the paperNot a substantial claim - Findingown data
β-caryophyllene synthase (CPS) is mostly expressed in young leaves and flower buds.
“Germacrene A and caryophyllene synthase were mostly expressed in young leaves and flower buds while epi-cedrol synthase was highly expressed in old leaves.”
Quote in the paperNot a substantial claim - Findingown data
Young leaves have a higher density of glandular trichomes than old leaves (approximately 300±40 vs 130±25 trichomes/cm2).
“From Figure 2, it is evident that young leaves (panels C and D) carry considerably higher density of trichomes than older leaves (panels E and F).”
- Also stated in: § Trichomes · hedged
“We have estimated, by counting trichomes, that on young leaves there are around 300±40 trichomes/cm2 while the corresponding number for old leaves was 130 ± 25 trichomes/cm2.”
Quote in the paperNot a substantial claim - Also stated in: § Trichomes · hedged
- Findingown data
Dihydroartemisinic aldehyde reductase (RED1) showed very high expression only in hairy root cultures.
“Further, dihydroartemisinic aldehyde reductase showed a very high expression only in hairy root cultures.”
Quote in the paperNot a substantial claim - Findingown data
RED1 is expressed only at low levels in tissues producing artemisinin.
“our results show that this enzyme is expressed only at low levels in tissues producing artemisinin”
Quote in the paperSubstantial claim
- Findingown data
Germacrene A synthase (GAS) is mostly expressed in young leaves and flower buds.
“Germacrene A and caryophyllene synthase were mostly expressed in young leaves and flower buds while epi-cedrol synthase was highly expressed in old leaves.”
Quote in the paperNot a substantial claim - Findingown data
FDS, SQS, and DXR showed only modest variation in expression in different tissues.
“Farnesyldiphosphate synthase, squalene synthase, and 1-deoxy-D-xylulose-5-phosphate reductoisomerase showed only modest variation in expression in the different tissues”
Quote in the paperNot a substantial claim - Findingown data
Epi-cedrol synthase (ECS) is highly expressed in old leaves.
“Germacrene A and caryophyllene synthase were mostly expressed in young leaves and flower buds while epi-cedrol synthase was highly expressed in old leaves.”
Quote in the paperNot a substantial claim - Findingown data
The four artemisinin biosynthetic pathway genes (ADS, CYP71AV1, DBR2, ALDH1) showed remarkably higher expression (between ~40- to ~500-fold) in flower buds and young leaves compared to other tissues (old leaves, stems, roots, hairy root cultures).
“The four genes of the artemisinin biosynthetic pathway (amorpha-4,11-diene synthase, amorphadiene-12-hydroxylase, artemisinic aldehyde ∆11(13) reductase and aldehyde dehydrogenase 1) showed remarkably higher expression (between ~40- to ~500-fold) in flower buds and young leaves compared to other tissues (old leaves, stems, roots, hairy root cultures).”
Quote in the paperSubstantial claim - Findingown data
DXS expression was 7-8-fold higher in flower buds and young leaves compared to old leaves.
“while expression of 1-deoxy-D-xylulose-5-phosphate synthase was 7-8-fold higher in flower buds and young leaves compared to old leaves.”
Quote in the paperNot a substantial claim - Findingown data
Total expression of FDS1/FDS2 is essentially the same in all tissues.
“From Figure 3 it is evident that the total expression of FDS1/FDS2 is essentially the same in all tissues”
Quote in the paperNot a substantial claim - Findingown data
ADS is the dominating sesquiterpene synthase in flower buds and young leaves.
“ADS is the dominating sesquiterpene synthase in flower buds and young leaves”
Quote in the paperSubstantial claim - Findingown data
In other tissues, DXS expression was equal to that in old leaves.
“In the other tissues, the expression of DXS was equal to that in old leaves.”
Quote in the paperNot a substantial claim - Findingown data
The four genes of artemisinin biosynthesis were highly expressed in flower buds and young leaves, tissues showing a high density of glandular trichomes.
“Four genes of artemisinin biosynthesis were highly expressed in flower buds and young leaves (tissues showing a high density of glandular trichomes).”
Quote in the paperSubstantial claim - Findingown data
HDR expression was 10-30-fold higher in old leaves than in the other tissues.
“The expression of HDR was 10-30-fold higher in old leaves than in the other tissues.”
Quote in the paperNot a substantial claim - Findingown data
In old leaves, ECS appears to be the only sesquiterpene synthase highly expressed.
“In old leaves, ECS appears to be the only sesquiterpene synthase highly expressed.”
Quote in the paperNot a substantial claim - Findingown data
Essentially no amorpha-4,11-diene is detected by GC-MS of a hexane extract from this variety of A. annua.
“essentially no amorpha-4,11-diene is detected by GC-MS of an hexane extract from this variety of A. annua (unpublished)”
Quote in the paperSubstantial claim - Findingown data
ALDH1 was almost not detectable in hairy roots.
“ALDH1 was almost not detectable in hairy roots”
Quote in the paperSubstantial claim - Findingown data
The combined expression of DBR2 and OPR3 is essentially the same in flower buds, young leaves, and old leaves.
“The combined expression of these two genes is essentially the same in flower buds, young leaves and old leaves (Figure 3; panels A and B).”
Quote in the paperNot a substantial claim - Findingown data
Expression of RED1 in hairy roots of A. annua was around 50 times more than in old leaves.
“a high expression of RED1 was observed in hairy roots of A. annua, i.e. around 50 times more than in old leaves (Figure 3E)”
Quote in the paperNot a substantial claim - Findingown data
Expression of RED1 in flower buds, young leaves and stems was relatively low and just a fraction of that observed in old leaves.
“Expression of RED1 in flower buds, young leaves and stems was relatively low and just a fraction of that observed in old leaves (Figure 3A-3C).”
Quote in the paperSubstantial claim - Findingown data
Four genes of the artemisinin biosynthetic pathway (ADS, CYP71AV1, DBR2 and ALDH1) showed 40- to 500-fold higher expression in flower buds and young leaves compared to other tissues (old leaves, stems, roots and hairy root cultures).
“four genes of the artemisinin biosynthetic pathway (ADS, CYP71AV1, DBR2 and ALDH1) showed remarkably higher expression (between 40- to 500-fold) in flower buds and young leaves compared to other tissues (old leaves, stems, roots and hairy root cultures) (Figure 3)”
Quote in the paperSubstantial claim - Findingown data
A significant amount of SQS was expressed in the tissues with high artemisinin biosynthesis.
“As seen in Table 5, a significant amount of SQS was expressed in the tissues with high artemisinin biosynthesis.”
Quote in the paperSubstantial claim - Findingown data
Expression of other sesquiterpene synthases was much lower than ADS in tissues producing artemisinin precursors (flower buds and young leaves).
“The expression of other sesquiterpene synthases was much lower than ADS in tissues producing artemisinin precursors (i.e. flower buds and young leaves).”
Quote in the paperSubstantial claim - Findingown data
Expression of SQS varied only modestly between different tissues in the qPCR study.
“The expression of SQS varied only modest between different tissues in our qPCR study.”
Quote in the paperNot a substantial claim - Findingnone given
RED1 activity was very low in artemisinin-producing tissues.
“the RED1 activity was very low in artemisinin-producing tissues”
Quote in the paperSubstantial claim - Interpretationown data
The effect of RED1 on artemisinin production may be limited.
“consequently its effect on artemisinin production may be limited.”
Quote in the paperSubstantial claim - Interpretationcitation
Additional sesquiterpene synthases are likely expressed in A. annua.
“However, it is likely that additional sesquiterpene synthases are expressed in A. annua since other classes of sesquiterpenes such as eudesmanes (e.g. β-selinene), guaianes (e.g. α-guaiene), longipinanes (e.g. β-longipinene) and santalanes (e.g. α-santalol) have been isolated from the plant [10].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Brown GD: The biosynthesis of artemisinin and the phytochemistry of Artemisia annua L. Molecules. 2010, 15: 7603-7698. 10.3390/molecules15117603. source
Not checked in the free run.
- Premisecitation
Artemisinin and a number of other terpenoids are produced in glandular secretory trichomes present on aerial surfaces of A. annua.
“Artemisinin and a number of other terpenoids are produced in glandular secretory trichomes present on aerial surfaces of the plant.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Duke SO, Paul RN: Development and fine structure of the glandular trichomes of Artemisia annua L. Int J Plant Sci. 1993, 154: 107-118. 10.1086/297096. source
Not checked in the free run.
- Interpretationreasoning
The activity of various sesquiterpene synthases may influence the yield of artemisinin in the plant.
“Consequently, the activity of various sesquiterpene synthases may influence the yield of artemisinin in the plant.”
Quote in the paperSubstantial claim - Study design and conductown data
The primer efficiencies used in the qPCR experiments were between 1.82 and 1.93.
“The efficiency of these primer pairs was calculated from the qPCR experiments and was found to be between 1.82 and 1.93 as summarized in Table 1.”
Quote in the paperNot a substantial claim - Premisecitation
It was shown by qPCR that levels of ADS, CYP71AV1, DBR2 and ALDH1 were around 50, 13, 160 and 55 times higher in isolated trichomes (from flower buds) than in leaves.
“It was shown by qPCR that the levels of ADS, CYP71AV1, DBR2 and ALDH1 were around 50, 13, 160 and 55 times higher in isolated trichomes (from flower buds) than in leaves, respectively [41]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Maes L, Van Nieuwerburgh FCW, Zhang Y, Reed DW, Pollier J, Vande Casteele SRF, Inzé D, Covello PS, Deforce DLD LD, Goossens A: Dissection of the phytohormonal regulation of trichome formation and biosynthesis of the antimalarial compound artemisinin in Artemisia annua plants. New Phytologist. 2011, 189: 176-189. 10.1111/j.1469-8137.2010.03466.x. source
Not checked in the free run.
- Interpretationreasoning
ADS is capable to channel a major part of the available substrate into artemisinin biosynthesis.
“It may be concluded that ADS is capable to channel a major part of the available substrate into artemisinin biosynthesis.”
Quote in the paperSubstantial claim - Interpretationnone given
Squalene synthase, but not other sesquiterpene synthases, appears to be a significant competitor for farnesyl diphosphate in artemisinin-producing tissues.
“Finally, squalene synthase but not other sesquiterpene synthases appears to be a significant competitor for farnesyl diphosphate in artemisinin-producing tissues.”
Quote in the paperSubstantial claim- Rests on an assumption: FDP is used for the synthesis of squalene, which is the precursor of sterols and triterpenes.
- Premisecitation
Upregulation of ADS by genetic transformation of A. annua resulted in an increased formation of artemisinin.
“Ma et al [2009] showed that upregulation of ADS by genetic transformation of A. annua resulted in an increased formation of artemisinin”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Ma C, Wang H, Lu X, Wang H, Xu G, Liu B: Terpenoid metabolic profiling analysis of transgenic Artemisia annua L. by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. Metabolomics. 2009, 5: 497-506. 10.1007/s11306-009-0170-6. source
Not checked in the free run.
- Interpretationreasoning
In this chemotype of A. annua, the activity of DBR2 is significantly higher than that of CYP71AV1.
“since dihydroartemisinic acid accumulates in this chemotype, we may conclude that the activity of DBR2 is significantly higher than that of CYP71AV1”
Quote in the paperSubstantial claim - Interpretationown data
The high expression levels of ADS, CYP71AV1, DBR2, and ALDH1 in flower buds and young leaves indicate a high capacity to produce artemisinin precursors in these tissues carrying biosynthetically active trichomes.
“These high expression levels indicate a high capacity to produce artemisinin precursors in these tissues carrying biosynthetically active trichomes.”
Quote in the paperSubstantial claim - Premisecitation
FDS1 is a housekeeping gene expressed in all tissues at all developmental stages.
“FDS1 is a housekeeping gene as it is expressed in all tissues at all developmental stages [28].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Cunillera N, Boronat A, Ferrer A: Spatial and temporal patterns of GUS expression directed by 5' regions of the Arabidopsis thaliana farnesyl diphosphate synthase genes FPS1 and FPS2. Plant Mol Biol. 2000, 44: 747-758. 10.1023/A:1026588708849. source
Not checked in the free run.
- Premisecitation
Upregulation of FDS by genetic transformation of A. annua using a constitutive promoter resulted in increased artemisinin production.
“upregulation of FDS by genetic transformation of A. annua using constitutive promoter resulted in an increased artemisinin production [29]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Han JL, Liu BY, Ye HC, Wang H, Li ZQ, Li GF: Effects of overexpression of the endogenouse farnesyl diphosphate synthase on the artemisinin content in Artemisia annua L. J Integr Plant Biol. 2006, 48: 482-487. 10.1111/j.1744-7909.2006.00208.x. source
Not checked in the free run.
- Interpretationcitation
FDS1 may be a rate-limiting enzyme in artemisinin biosynthesis.
“indicating that FDS1 also may be a rate-limiting enzyme in artemisinin biosynthesis”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Han JL, Liu BY, Ye HC, Wang H, Li ZQ, Li GF: Effects of overexpression of the endogenouse farnesyl diphosphate synthase on the artemisinin content in Artemisia annua L. J Integr Plant Biol. 2006, 48: 482-487. 10.1111/j.1744-7909.2006.00208.x. source
Not checked in the free run.
- The authors state this as an assumption: Only one percent of the FDS1 activity is found in trichome cells.
- Interpretationcitation
RED1 does not appear to have any significant influence on the biosynthesis of artemisinin.
“Next it may be concluded that RED1 does not appear to have any significant influence on the biosynthesis of artemisinin”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Rydén A-M, Ruyter-Spira C, Quax WJ, Osada H, Muranaka T, Kayser O, Bouwmeester H: The Molecular cloning of dihydroartemisinic aldehyde reductase and its implication in artemisinin biosynthesis in Artemisia annua. Planta Med. 2010, 76 (15): 1778-1783. source
Not checked in the free run.
- Interpretationreasoning
DBR2 and ALDH1 are present in excess assuming they act on the same pool of intermediates.
“the other trichome-specific enzymes DBR2 and ALDH1 (Figure 3) are present in excess assuming that they are acting on the same pool of intermediates.”
Quote in the paperSubstantial claim- The authors state this as an assumption: DBR2 and ALDH1 are acting on the same pool of intermediates.
- Interpretationreasoning
ALDH1 exhibits a 5-fold higher potential conversion of dihydroartemisinic aldehyde compared to artemisinic aldehyde.
“Due to differences in the kcat-value, ALDH1 exhibits a 5-fold higher potential conversion of dihydroartemisinic aldehyde as compared to artemisinic aldehyde (Table 4).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: The number of active sites is proportional to the level of transcription.
- The authors state this as an assumption: The enzymes are working at substrate saturation with an optimal NADPH/NADP+ ratio.
- The authors state this as an assumption: Under these conditions, the kcat-value is a good indicator of the conversion of substrate to product.
- Premisecitation
The yield of artemisinin in hairy roots is relatively low.
“the yield of artemisinin in hairy roots, which is relatively low [43,44]”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [43] Liu CZ, Wang YC, Ouyang F, Ye HC, Li GF: Production of artemisinin by hairy root cultures of Artemisia annua L. Biotechnol Lett. 1997, 19: 927-929. 10.1023/A:1018362309677. source
Not checked in the free run.
- cites [44] Weathers PJ, Bunk G, McCoy MC: The effect of phytohormones on growth and artemisinin production in Artemisia annua hairy root. In Vitro Cell Dev Biol - Plant. 2005, 41: 47-53. 10.1079/IVP2004604. source
Not checked in the free run.
- Interpretationreasoning
The small variation in FDS1/FDS2 expression may be explained by FDS1 being a housekeeping gene constituting a major part of total FDS1/FDS2, masking different FDS2 expression.
“the relatively small variation observed may be explained by the fact that the housekeeping gene FDS1 constitutes a major part of total FDS1/FDS2 and that the eventual different level of FDS2 expression in different tissues thereby becomes masked.”
Quote in the paperSubstantial claim - Interpretationreasoning
ADS is a rate-limiting enzyme due to its low kcat-value.
“It may be concluded that ADS is a rate-limiting enzyme due to its low kcat-value”
Quote in the paperSubstantial claim- The authors state this as an assumption: The number of active sites is proportional to the level of transcription.
- The authors state this as an assumption: The enzymes are working at substrate saturation with an optimal NADPH/NADP+ ratio.
- The authors state this as an assumption: Under these conditions, the kcat-value is a good indicator of the conversion of substrate to product.
- Interpretationcitation
ADS is a rate-limiting enzyme in artemisinin biosynthesis.
“showing that ADS is a rate-limiting enzyme [46]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Ma C, Wang H, Lu X, Wang H, Xu G, Liu B: Terpenoid metabolic profiling analysis of transgenic Artemisia annua L. by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. Metabolomics. 2009, 5: 497-506. 10.1007/s11306-009-0170-6. source
Not checked in the free run.
- Interpretationcitation
The genes encoding enzymes of artemisinin biosynthesis are specifically expressed in trichomes.
“which once again shows that the genes encoding enzymes of artemisinin biosynthesis are specifically expressed in trichomes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Maes L, Van Nieuwerburgh FCW, Zhang Y, Reed DW, Pollier J, Vande Casteele SRF, Inzé D, Covello PS, Deforce DLD LD, Goossens A: Dissection of the phytohormonal regulation of trichome formation and biosynthesis of the antimalarial compound artemisinin in Artemisia annua plants. New Phytologist. 2011, 189: 176-189. 10.1111/j.1469-8137.2010.03466.x. source
Not checked in the free run.
- Premisecitation
Down-regulation of SQS by hairpin-RNA-mediated gene silencing in A. annua resulted in a 3-fold increased artemisinin production.
“Zhang et al. showed that down-regulation of SQS by hairpin-RNA-mediated gene silencing in A. annua resulted in a 3-fold increased artemisinin production [49].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Zhang L, Jing F, Li F, Li M, Wang Y, Wang G, Sun X, Tang K: Development of transgenic Artemisia annua (Chinese wormwood) plants with an enhanced content of artemisinin, an effective anti-malarial drug, by hairpin-RNA-mediated gene silencing. Biotechnol Appl Biochem. 2009, 52: 199-207. 10.1042/BA20080068. source
Not checked in the free run.
- Interpretationreasoning
In this chemotype of A. annua, the turnover capacity of DBR2 is apparently sufficient to convert most of the artemisinic aldehyde to dihydroartemisinic aldehyde for further conversion to artemisinin.
“in this chemotype of A. annua, the turnover capacity of DBR2 is apparently sufficient to convert most of the artemisinic aldehyde to dihydroartemisinic aldehyde for further conversion to artemisinin”
Quote in the paperSubstantial claim - Interpretationreasoning
The fraction of SQS expressed in trichome cells may channel part of available FDP into sterols and thereby lower the yield of artemisinin.
“The fraction of SQS expressed in trichome cells may channel part of available FDP into sterols and thereby lower the yield of artemisinin.”
Quote in the paperSubstantial claim - Interpretationown data
The influence of other sesquiterpene synthases on artemisinin yield appears relatively limited.
“their influence on artemisinin yield appear to be relatively limited”
Quote in the paperSubstantial claim - Interpretationreasoning
RED1 appears not to influence the yield of the artemisinin precursor dihydroartemisinic acid to any significant extent.
“this enzyme appears not to influence the yield of the artemisinin precursor dihydroartemisinic acid to any significant extent”
Quote in the paperSubstantial claim - Interpretationreasoning
The potential utilization of FDP by SQS is most likely higher than that of ADS.
“the potential utilization of FDP by SQS is most likely higher than that of ADS”
Quote in the paperSubstantial claim- The authors state this as an assumption: The kcat-value for A. annua SQS is in the order of 1 sec-1.
- Interpretationreasoning
The ratio of CYP71AV1 and DBR2 may be critical for the type of end product formed.
“the ratio of CYP71AV1 and DBR2 may be critical for the type of end product formed”
Quote in the paperSubstantial claim - Interpretationreasoning
Downregulation of other sesquiterpene synthase(s) will most likely not affect artemisinin production in A. annua.
“downregulation of other sesquiterpene synthase(s) will most likely not affect artemisinin production in A. annua”
Quote in the paperSubstantial claim - Interpretationreasoning
Squalene synthesis may influence the yield of artemisinin.
“squalene synthesis may influence the yield of artemisinin”
Quote in the paperSubstantial claim - Interpretationown data
The higher capacity to produce artemisinin precursors in flower buds and young leaves is partly due to the considerably higher density of trichomes on these tissues.
“which is partly due to the considerably higher density of trichomes on these tissues (Figure 2)”
Quote in the paperSubstantial claim - Study design and conductown data
Based on BestKeeper, the genes CPR, β-actin and PAL were selected as reference genes.
“Based on BestKeeper, the genes CPR, β-actin and PAL were selected as reference genes.”
Quote in the paperSubstantial claim - Interpretationreasoning
Flower buds and young leaves have a much higher capacity to produce artemisinin precursors.
“These high expression levels indicate a much higher capacity to produce artemisinin precursors in flower buds and young leaves”
Quote in the paperSubstantial claim
- May combine two claims. 25
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 30
May combine two claims.
Findingown dataCYP71AV1 expression was ~150-fold higher in flower buds and ~150-fold higher in young leaves compared to old leaves.
“i.e. ~500 and ~150 times more ADS, ~150 and ~150 times more CYP71AV1, ~40 and ~70 times more DBR2 and ~250 and ~130 times more ALDH1 in flower buds and young leaves, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataADS expression was ~500-fold higher in flower buds and ~150-fold higher in young leaves compared to old leaves.
“i.e. ~500 and ~150 times more ADS, ~150 and ~150 times more CYP71AV1, ~40 and ~70 times more DBR2 and ~250 and ~130 times more ALDH1 in flower buds and young leaves, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataALDH1 expression was ~250-fold higher in flower buds and ~130-fold higher in young leaves compared to old leaves.
“i.e. ~500 and ~150 times more ADS, ~150 and ~150 times more CYP71AV1, ~40 and ~70 times more DBR2 and ~250 and ~130 times more ALDH1 in flower buds and young leaves, respectively.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataHMGR expression was around 20-fold higher in flower buds, 8-fold higher in young leaves, and 20-fold higher in roots than in old leaves.
“around 20- and 8-fold more expression was seen in highly biosynthetically active flower buds and young leaves, respectively, than in old leaves (Figure 3).”
- Also stated in: § Gene expression · plain
“HMGR also was enhanced 20-fold in roots.”
Quote in the paperSubstantial claim- Also stated in: § Gene expression · plain
May combine two claims.
Findingown dataTranscripts of all 14 genes studied were detected in all tissues at different amounts by qPCR, except ADS was not detected in roots.
“Transcripts of all the genes studied could be detected in all tissues at different amounts using qPCR. The only exception was that no ADS could be detected in roots.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDBR2 expression was ~40-fold higher in flower buds and ~70-fold higher in young leaves compared to old leaves.
“i.e. ~500 and ~150 times more ADS, ~150 and ~150 times more CYP71AV1, ~40 and ~70 times more DBR2 and ~250 and ~130 times more ALDH1 in flower buds and young leaves, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGlandular trichomes are present in all aerial tissues (flower buds, leaves, stems) at different densities but not on roots or hairy root cultures.
“glandular trichomes of A. annua were visualized by fluorescence microscopy (Figure 2) and found in all aerial tissues of the plant such as flower buds (panels A and B), leaves (panels C-F), stems (panels G and H) at different densities, but as expected not on roots (panels I and J) or hairy root cultures of A. annua (panels K and L).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenNo ADS could be detected in roots of A. annua, while small amounts were found in hairy roots.
“Finally, no ADS could be detected in roots of A. annua while small amounts were found in hairy roots.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
FindingcitationRED1 has low relative turnover potential.
“low relative turnover potential”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
FindingcitationRED1 is only partially localized to trichomes.
“only partial localization to trichomes”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe two FDS genes from A. annua show 96.6% nucleotide sequence identity and the amplified segment is identical in the two genes.
“The two FDS genes from A. annua show 96.6% nucleotide sequence identity and the segment that was amplified with the primers used (Table 1) is identical in the two genes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDXR expression appears somewhat enhanced in flower buds and hairy roots but lower in stems and roots.
“The expression of DXR appears to be somewhat enhanced in flower buds and hairy roots but lower in stems and roots.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataExpression of ECS was much lower in flower buds and young leaves than in old leaves, while expression of CPS and GAS was considerably higher in flower buds and young leaves compared to old leaves.
“The expression of ECS was much lower in flower buds and young leaves than in old leaves (Figure 3A and 3B), while expression of CPS and GAS was considerably higher in these tissues as compared to old leaves.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDihydroartemisinic acid is formed from artemisinic aldehyde in two steps via dihydroartemisinic aldehyde, catalyzed by DBR2 and ALDH1.
“Dihydroartemisinic acid is formed from artemisinic aldehyde in two steps via dihydroartemisinic aldehyde. The reduction is catalyzed by artemisinic aldehyde Δ11(13) reductase (DBR2) [15] and the oxidation to the acid by aldehyde dehydrogenase 1 (ALDH1) [16].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Zhang Y, Teoh KH, Reed DW, Maes L, Goossens A, Olson DJ, Ross AR, Covello PS: The molecular cloning of artemisinic aldehyde Δ11(13) reductase and its role in glandular trichome-dependent biosynthesis of artemisinin in Artemisia annua. J Biol Chem. 2008, 283: 21501-21508. 10.1074/jbc.M803090200. source
Not checked in the free run.
- cites [16] Teoh KH, Polichuk DR, Reed DW, Covello PS: Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemsia annua. Botany. 2009, 87: 635-642. 10.1139/B09-032. source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationFive different sesquiterpene synthases (ECS, ADS, CPS, GAS, and BFS) have been cloned from A. annua.
“so far five different sesquiterpene synthases (epi-cedrol synthase (ECS) [5], amorpha-4,11-diene synthase (ADS) [6]; β-caryophyllene synthase (CPS) [7], germacrene A synthase (GAS) [8] and β-farnesene synthase (BFS) [9] have been cloned from the plant.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Mercke P, Crock J, Croteau R, Brodelius PE: Cloning, expression and characterization of epi-cedrol synthase, a sesquiterpene cyclase from Artemisia annua L. Arch Biochem Biophys. 1999, 369: 213-222. 10.1006/abbi.1999.1358. source
Not checked in the free run.
- cites [6] Mercke P, Bengtsson M, Bouwmeester HJ, Posthumus MA, Brodelius PE: Molecular cloning, expression, and characterization of amorpha-4,11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L. Arch Biochem Biophys. 2000, 381: 173-180. 10.1006/abbi.2000.1962. source
Not checked in the free run.
- cites [7] Cai Y, Jia J-W, Crock J, Lin Z-X, Chen X-Y, Croteau R: A cDNA clone for β-caryophyllene synthase from Artemisia annua. Phytochemistry. 2002, 61: 523-529. 10.1016/S0031-9422(02)00265-0. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDihydroartemisinic acid, not artemisinic acid, is the precursor of artemisinin.
“recent feeding experiments with artemisinic acid [13] and dihydroartemisinic acid [14] have shown that the latter substance is the precursor of artemisinin.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [13] Brown GD, Sy LK: In vivo transformations of artemisinic acid in Artemisia annua plants. Tetrahedron. 2006, 63: 9548-9566. 10.1016/j.tet.2007.06.062. source
Not checked in the free run.
- cites [14] Brown GD, Sy LK: In vivo transformations of dihydroartemisinic acid in Artemisia annua plants. Tetrahedron. 2004, 60: 1139-1159. 10.1016/j.tet.2003.11.070. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe production of specific terpenoids, including artemisinin, takes place within the secretory cells of glandular trichomes.
“it is well established that the production of specific terpenoids, including artemisinin, takes place within the secretory cells of such trichomes [21,22].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [21] Ferreira JFS, Janick J: Distribution of artemisinin in Artemisia annua. Progress in new crops. Edited by: Janick J. Arlington: ASHS Press; 1996,579-584.
Not checked in the free run.
- cites [22] Tellez MR, Canel C, Rimando AM, Duke SO: Differential accumulation of isoprenoids in glanded and glandless Artemisia annua L. Phytochemistry. 1999, 52: 1035-1040. 10.1016/S0031-9422(99)00308-8. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe first committed step in artemisinin biosynthesis is the conversion of FDP to amorpha-4,11-diene by ADS.
“The first committed step in artemisinin biosynthesis is the conversion of FDP to amorpha-4,11-diene by ADS [6,11].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Mercke P, Bengtsson M, Bouwmeester HJ, Posthumus MA, Brodelius PE: Molecular cloning, expression, and characterization of amorpha-4,11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L. Arch Biochem Biophys. 2000, 381: 173-180. 10.1006/abbi.2000.1962. source
Not checked in the free run.
- cites [11] Bouwmeester HJ, Wallaart TE, Janssen MH, van Loo B, Jansen BJ, Posthumus MA, Schmidt CO, de Kraker JW, Konig WA, Franssen MC: Amorpha-4, 11-diene synthase catalyses the first probable step in artemisinin biosynthesis. Phytochemistry. 1999, 52: 843-854. 10.1016/S0031-9422(99)00206-X. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe conversion of dihydroartemisinic acid to artemisinin is believed to be a non-enzymatic spontaneous reaction.
“The conversion of dihydroartemisinic acid to artemisinin is believed to be a non-enzymatic spontaneous reaction [14].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Brown GD, Sy LK: In vivo transformations of dihydroartemisinic acid in Artemisia annua plants. Tetrahedron. 2004, 60: 1139-1159. 10.1016/j.tet.2003.11.070. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe genetic variation within A. annua appears high; at least two chemotypes with different essential oil compositions have been described.
“The genetic variation within A. annua appears to be high. At least two chemotypes with different compositions of the essential oil during the vegetative period have been described [19].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Wallaart TE, Pras N, Beekman AC, Quax WJ: Seasonal variation of artemisinin and its biosynthetic precursors in plants of Artemisia annua of different geographical origin; proof for the existence of chemotypes. Planta Med. 2000, 66: 57-62. 10.1055/s-2000-11115. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAmorpha-4,11-diene is hydroxylated to artemisinic alcohol by the cytochrome P450 dependent hydroxylase CYP71AV1.
“In the following step, amorpha-4,11-diene is hydroxylated to yield artemisinic alcohol. This reaction is catalyzed by a cytochrome P450 dependent hydroxylase (CYP71AV1) [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Teoh KH, Polichuk DR, Reed DW, Nowak G, Covello PS: Artemisia annua L. (Asteraceae) trichome-specific cDNAs reveal CYP71AV1, a cytochrome P450 with a key role in the biosynthesis of the antimalarial sesquiterpene lactone artemisinin. FEBS Lett. 2006, 580: 1411-1416. 10.1016/j.febslet.2006.01.065. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThere is no conversion in planta of artemisinic acid to dihydroartemisinic acid or vice versa.
“According to previous investigations, there is no conversion in planta of artemisinic acid to dihydroartemisinic acid or vice versa [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Brown GD, Sy LK: In vivo transformations of artemisinic acid in Artemisia annua plants. Tetrahedron. 2006, 63: 9548-9566. 10.1016/j.tet.2007.06.062. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe major components of the essential oil from A. annua are mono- and sesquiterpenes produced in trichomes.
“The major components of the essential oil from A. annua are mono- and sesquiterpenes produced in trichomes [4].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Simon JE, Charles D, Cebert E, Grant L, Janick J, Whipkey A: Artemisia annua L.: a promising aromatic and medicinal. Advances in new crops. Edited by: Janick J and Simon JE. Portland: Timber Press; 1990, 522-526.
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataThree reference genes were used to calculate expression ratios for the 14 transcripts monitored.
“In total, 14 different transcripts have been monitored using three reference genes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataAll graphs represent two independent qPCR runs with cDNA prepared from different plants, with sample triplicates in all qPCR runs.
“All graphs represent the values of two independent qPCR runs with cDNA prepared from different plants. Sample triplicates were used in all qPCR runs.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningAll these sesquiterpene synthases may compete for the same substrate, farnesyl diphosphate (FDP), which is a precursor of artemisinin.
“All these sesquiterpene synthases may compete for the same substrate, farnesyl diphosphate (FDP), which is a precursor of artemisinin.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe yield of terpenoids in various plants is highly dependent on trichome abundance.
“Furthermore the yield of terpenoids in various plants is highly dependent on trichome abundance [23].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Biswas KK, Foster AJ, Aung T, Mahmoud SS: Essential oil production: relationship with abundance of glandular trichomes in aerial surface of plants. Acta Physiol Plant. 2009, 31: 13-19. 10.1007/s11738-008-0214-y. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenTwo independent triplet reactions were used for the calculation of average CT-values.
“Two independent triplet reactions were used for the calculation of average CT-values.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDXS plays a major role in the overall regulation of the MEP pathway.
“It is well established that DXS, the first enzyme of the MEP pathway, plays a major role in the overall regulation of the pathway [33].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Cordoba E, Salmi M, León P: Unravelling the regulatory mechanisms that modulate the MEP pathway in higher plants. J Exp Bot. 2009, 60: 2933-2943. 10.1093/jxb/erp190. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationStermer et al. showed that HMGR activity is much reduced in mature tissues.
“Stermer et al. showed that the HMGR activity is much reduced in mature tissues, correlating well with the results presented here [27].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Stermer BA, Bianchini GM, Korth KL: Regulation of HMG-CoA reductase activity in plants. J Lipid Res. 1994, 35: 1133-1140. source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationOne C5-unit of FDP, the precursor of artemisinin, is produced by the MEP pathway.
“it has recently been shown that one C5-unit of FDP, the precursor of artemisinin, is produced by the MEP pathway [34].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Schramek N, Wang H, Römisch-Margl W, Keil B, Radykewicz T, Winzenhörlein B, Beerhues L, Bacher A, Rohdich F, Gershenzon J, Liu B, Eisenreich W: Artemisinin biosynthesis in growing plants of Artemisia annua. A 13CO2 study. Phytochemistry. 2010, 71: 179-187. 10.1016/j.phytochem.2009.10.015. source
Not checked in the free run.
May combine two claims.
PremisecitationHMGR is a rate-limiting enzyme of the mevalonate pathway and HMGR expression limits artemisinin formation in A. annua.
“HMGR is a rate-limiting enzyme of the mevalonate pathway [24,25], and recently it has been shown that HMGR expression limits artemisinin formation in A. annua [26].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [24] Chappell J, Wolf F, Proulx J, Cuellar R, Saunders C: Is the reaction catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase a rate-limiting step for isoprenoid biosynthesis in plants?. Plant Physiol. 1995, 109: 1337-1343. source
Not checked in the free run.
- cites [25] Schaller H, Grausem B, Benveniste P, Chye M-L, Tan CT, Song Y-H, Chua N-H: Expression of the Hevea brasiliensis (H.B.K.) müll. Arg. 3-hydroxy-3-methylglutaryl coenzyme A reductase 1 in tobacco results in sterol overproduction. Plant Physiol. 1995, 109: 761-770. source
Not checked in the free run.
- cites [26] Ram M, Khan MA, Jha P, Khan S, Kiran U, Ahmad MM, Javed S, Abdin MZ: HMG-CoA reductase limits artemisinin biosynthesis and accumulation in Artemisia annua L. plants. Acta Physiol Plant. 2010, 32: 859-866. 10.1007/s11738-010-0470-5. source
Not checked in the free run.
May combine two claims.
Interpretationown dataOnly part of the FDS1/FDS2 activity is present in trichomes and involved in artemisinin biosynthesis.
“From Figure 3, we may conclude that only part of the FDS1/FDS2 activity is present in trichomes and involved in artemisinin biosynthesis.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationRED1 has a high Km for dihydroartemisinic aldehyde.
“due to a high Km for dihydroartemisinic aldehyde”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Rydén A-M, Ruyter-Spira C, Quax WJ, Osada H, Muranaka T, Kayser O, Bouwmeester H: The Molecular cloning of dihydroartemisinic aldehyde reductase and its implication in artemisinin biosynthesis in Artemisia annua. Planta Med. 2010, 76 (15): 1778-1783. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe relative amount of the biosynthetic enzymes is much higher in young trichomes, and the regulation of expression of these enzymes appears to be linked to the developmental stage of the trichomes.
“Obviously, the relative amount of the biosynthetic enzymes is much higher in young trichomes, and the regulation of expression of these enzymes appears to be linked to the developmental stage of the trichomes.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationArtemisinic acid and arteannuin B have been isolated from hairy root cultures of A. annua.
“These compounds have been isolated from hairy root cultures of A. annua [45].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Banerjee S, Zehra M, Gupta MM, Kumar S: Agrobacterium rhizogenes-mediated transformation of Artemisia annua: production of transgenic plants. Planta Med. 1997, 63: 467-469. 10.1055/s-2006-957737. source
Not checked in the free run.
May combine two claims.
Interpretationown dataAs amorpha-4,11-diene is formed by ADS, it is efficiently converted all the way to dihydroartemisinic acid, which accumulates in this chemotype of A. annua.
“it may be assumed that as amorpha-4,11-diene is formed by ADS, it is efficiently converted all the way to dihydroartemisinic acid, which accumulates in this chemotype of A. annua”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFDS2 is often inducible, found in special tissues at particular stages of development, and involved in phytoalexin biosynthesis.
“FDS2 is often inducible and found in special tissues at particular stages of development [28] and is also involved in phytoalexin biosynthesis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Cunillera N, Boronat A, Ferrer A: Spatial and temporal patterns of GUS expression directed by 5' regions of the Arabidopsis thaliana farnesyl diphosphate synthase genes FPS1 and FPS2. Plant Mol Biol. 2000, 44: 747-758. 10.1023/A:1026588708849. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataThe original number of trichomes seems to be spread out on a larger surface as the leaf expands with age.
“The original number of trichomes seem to be spread out on a larger surface as the leaf expands with age.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationOverexpression of FDS1 in A. annua results in an increase in artemisinin production, indicating it is a rate-limiting enzyme in this pathway.
“Overexpression of FDS1 in A. annua results in an increase in artemisinin production [29,30] indicating that it is a rate-limiting enzyme in this pathway.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [29] Han JL, Liu BY, Ye HC, Wang H, Li ZQ, Li GF: Effects of overexpression of the endogenouse farnesyl diphosphate synthase on the artemisinin content in Artemisia annua L. J Integr Plant Biol. 2006, 48: 482-487. 10.1111/j.1744-7909.2006.00208.x. source
Not checked in the free run.
- cites [30] Banyai W, Kirdmanee C, Mii M, Supaibulwatana K: Overexpression of farnesyl pyrophosphate synthase (FPS) gene affected artemisinin content and growth of Artemisia annuaL. Plant Cell Tiss Organ Cult.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDXR and HDR may have rate-limiting roles for the production of IDP and DMADP.
“DXR and HDR may also have rate-limiting roles for the production of IDP and DMADP [33].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Cordoba E, Salmi M, León P: Unravelling the regulatory mechanisms that modulate the MEP pathway in higher plants. J Exp Bot. 2009, 60: 2933-2943. 10.1093/jxb/erp190. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitationBestKeeper software was used to search for stable reference genes among all genes tested.
“The BestKeeper software [52] was used to search for stable reference genes among all genes tested.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] Pfaffl MW, Tichopád A, Prgomet C, Neuvians TP: Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper - Excel-based tool using pair-wise correlations. Biotechnol Lett. 2004, 26: 509-515. 10.1023/B:BILE.0000019559.84305.47. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenTriplets of all samples were run, and a negative control of the Master Mix in addition of primers was performed in all qPCR runs.
“Triplets of all samples were run, and a negative control of the Master Mix in addition of primers was performed in all qPCR runs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAny outliers in the triplets were detected by Grubbs test and removed.
“Any outliers in the triplets were detected by Grubbs test and removed.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAssuming a kcat of about 1 s-1 for A. annua SQS, the turnover potential of FDP to products for SQS is about 45-fold higher than that of ADS in flower buds and 25-fold higher in young leaves.
“Assuming a kcat-value for the A. annua SQS in the order of 1 sec-1 (= 2 FDPs used per second), results in about 45- and 25-fold higher turnover potential, of FDP to products, for SQS, as compared to the turnover potential of ADS in flower buds and young leaves, respectively.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The kcat-value for A. annua SQS is in the order of 1 sec-1.
May combine two claims.
InterpretationreasoningHigh DBR2 activity will result in an efficient formation of dihydroartemisinic aldehyde, dihydroartemisinic acid and artemisinin, while high CYP71AV1 activity may result in artemisinic acid and arteannuin B.
“high DBR2 activity will result in an efficient formation of dihydroartemisinic aldehyde, dihydroartemisinic acid and artemisinin while high CYP71AV1 activity may result in artemisinic acid and arteannuin B”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe A. annua SQS enzyme has been cloned and is similar to the enzymes from A. thaliana and Nicotiana tabacum.
“The A. annua enzyme has been cloned and is similar to the enzymes from A. thaliana and Nicotiana tabacum [48].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Liu CZ, Ye HC, Wang H, Li GF: Molecular cloning, Escherichia coli expression and genomic organization of squalene synthase gene from Artemisia annua. Acta Bot Sin. 2003, 45: 608-613.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA kcat of 3.3 s-1 has been reported for a soluble recombinant yeast SQS enzyme.
“a kcat = 3.3 sec-1 has been reported for a soluble recombinant yeast enzyme [47]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Zhang D, Jennings SM, Robinson GW, Poulter CD: Yeast squalene synthase: Expression, purification and characterization of soluble recombinant enzyme. Arch Biochem Biophys. 1993, 304: 133-143. 10.1006/abbi.1993.1331. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitationThe mean efficiency of the amplicons was calculated by Linreg v. 12.1 based on the log linear phase of the amplification curve.
“The mean efficiency of the amplicons was calculated by the program Linreg v. 12.1 based on the log linear phase of the amplification curve [51].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Ruijter JM, Ramakers C, Hoogaars WMH, Karlen Y, Bakker O, van den Hoff MJB, Moorman AFM: Amplification efficiancy, linking baseline and bias in the analysis of quantitative PCR data. Nucl Acids Res. 2009, 37: e45-10.1093/nar/gkp045. source
Not checked in the free run.
The authors state this as an assumption.
The number of active sites is proportional to the level of transcription.
“we assume that the number of active sites is proportional to the level of transcription”
The authors state this as an assumption.
The enzymes are working at substrate saturation with an optimal NADPH/NADP+ ratio.
“that the enzymes are working at substrate saturation with an optimal NADPH/NADP+ ratio”
The authors state this as an assumption.
Under these conditions, the kcat-value is a good indicator of the conversion of substrate to product.
“Under such conditions the kcat-value is a good indicator of the conversion of substrate to product.”
The authors state this as an assumption.
DBR2 and ALDH1 are acting on the same pool of intermediates.
“assuming that they are acting on the same pool of intermediates”
The paper relies on this without support.
FDP is used for the synthesis of squalene, which is the precursor of sterols and triterpenes.
“In addition, FDP is used for the synthesis of squalene, which is the precursor of sterols and triterpenes.”
The authors state this as an assumption.
Only one percent of the FDS1 activity is found in trichome cells.
“If we assume that only one percent of the FDS1 activity is found in trichome cells”
The authors state this as an assumption.
The kcat-value for A. annua SQS is in the order of 1 sec-1.
“Assuming a kcat-value for the A. annua SQS in the order of 1 sec-1 (= 2 FDPs used per second)”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
These and other changes were largely restricted to the juvenile leaves.
“These and other changes were largely restricted to the juvenile leaves (Supplemental T ables 1 and 2, Fig S5) which are relatively dense in glandular trichomes (29) and exhibit high expression levels of terpene synthases (30).”
From <i>Artemisia annua</i> mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Claim of no root expression conflicts with Table 3
MinorThe text says the biosynthetic enzymes listed in Table 3 are not expressed in roots, but the table marks CYP71AV1 as expressed in roots.
“It may, however, be concluded from Table 3 that the biosynthetic enzymes are expressed in flower buds, leaves and stems that carry glandular trichomes but not in roots.”
“| CYP71AV1 | +++++ | +++ | + | n.d. | + | RT-PCR | [12] |”
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Pfaffl, M. W. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.9.e36 · Cited by 7,377 · see citing works
Pfaffl, M. W., Tichopad, A., Prgomet, C., & Neuvians, T. P. (2004) · Biotechnology Letters · doi:10.1023/b:bile.0000019559.84305.47 · Cited by 5,065 · see citing works
Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data
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- Authors
- Olofsson, L., Engström, A., Lundgren, A., & Brodelius, P. E.
- Affiliations
- Linnaeus University (SE)
- Corresponding author
- Brodelius, Peter E
- ORCID
- Brodelius, Peter E
- Venue
- BMC Plant Biology
- Published
- 2011-03-09
- Volume
- 11
- Issue
- 1
- Pages
- 45-45
- ISSN
- 1471-2229 (ISSN-L)
- PMC
- PMC3063820
- OpenAlex
- W2152443621
- Semantic Scholar
- e41f2ceecfaa54b3effd7809549e01ce6db0e30a
- Cited by
- 144
- References
- 58
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 5 · 2019: 10 · 2018: 6 · 2017: 10 · 2016: 18 · 2015: 13 · 2014: 12 · 2013: 15 · 2012: 10
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Plant Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Mahidol University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant tissue culture and regeneration
- Keywords
- Artemisia annua, artemisinin biosynthesis, terpene metabolism, gene expression, tissue-specific gene expression, amorpha-4,11-diene synthase, ALDH1, germacrene A synthase, HMGR, farnesyl diphosphate synthase, squalene synthase, 1-deoxy-D-xylulose 5-phosphate synthase, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, hairy root culture
- MeSH terms
- Aldehyde Dehydrogenase 1 Family, Isoenzymes, Oxidoreductases, Plant Proteins, Gene Expression Regulation, Plant, RNA, Plant, Alkyl and Aryl Transferases, Gene Expression Profiling, Artemisia annua, Artemisinins, Retinal Dehydrogenase
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