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taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2 = taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2 = taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
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taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2 = taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
reaction mechanism
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2 = taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
requires P450, reaction includes rearrangement of the 4(5)-double bound to a 4(20)-double bond, possibly through allylic oxidation, proposed mechanism
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taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2 = taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
requires P450, reaction includes rearrangement of the 4(5)-double bound to a 4(20)-double bond, possibly through allylic oxidation, proposed mechanism
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taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2 = taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
mechanism involving promiscuous radical abstraction with selective oxygen insertion
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taxa-4(20),11(12)-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11(12)-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: preferred substrate
Products: -
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taxa-4(20)-11(12)-diene + AH2 + O2
?
Taxus sp.
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Substrates: -
Products: -
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taxa-4(5),11(12)-diene + [reduced NADPH-hemoprotein reductase] + O2
5(12)-oxa-3(11)-cyclotaxane + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: hydroxylation of the C-5alpha is the first of the oxidations resulting in taxol
Products: OCT is a cyclic ether
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taxa-4(5),11(12)-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11(12)-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11(12)-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Taxus sp.
-
Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
taxadiene + [reduced NADPH-hemoprotein reductase] + O2
taxadiene-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: -
Products: -
?
additional information
?
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taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
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Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
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Substrates: reaction is completely dependent on NADPH
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
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Substrates: reaction is completely dependent on NADPH, enzyme catalyzes the first oxygenating step in taxol biosynthesis pathway
Products: -
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taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
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Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
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Substrates: reaction is completely dependent on NADPH
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
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Substrates: reaction is completely dependent on NADPH, enzyme catalyzes the first oxygenating step in taxol biosynthesis pathway
Products: -
?
additional information
?
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Substrates: the recombinant enzyme produces 5(12)-oxa-3(11)-cyclotaxane, a tritiated oxidized taxane, instead of taxa-4(20),11-dien-5alpha-ol, structural analysis of the compound, overview
Products: -
?
additional information
?
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Substrates: cDNAs encoding taxa-4(5),11(12)-diene synthase and CYP725A4 are introduced in Nicotiana sylvestris for specific expression in trichome cells. The co-expression does not lead to the production of the expected 5-hydroxytaxa-4(20),11(12)-diene. Instead, taxa-4(5),11(12)-diene is quantitatively converted to a novel taxane
Products: -
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taxa-4(20)-11(12)-diene + AH2 + O2
?
Taxus sp.
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Substrates: -
Products: -
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taxa-4(5),11(12)-diene + [reduced NADPH-hemoprotein reductase] + O2
5(12)-oxa-3(11)-cyclotaxane + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: hydroxylation of the C-5alpha is the first of the oxidations resulting in taxol
Products: OCT is a cyclic ether
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11(12)-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Taxus sp.
-
Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
taxadiene + [reduced NADPH-hemoprotein reductase] + O2
taxadiene-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: -
Products: -
?
additional information
?
-
Substrates: cDNAs encoding taxa-4(5),11(12)-diene synthase and CYP725A4 are introduced in Nicotiana sylvestris for specific expression in trichome cells. The co-expression does not lead to the production of the expected 5-hydroxytaxa-4(20),11(12)-diene. Instead, taxa-4(5),11(12)-diene is quantitatively converted to a novel taxane
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
-
Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
-
Substrates: reaction is completely dependent on NADPH, enzyme catalyzes the first oxygenating step in taxol biosynthesis pathway
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
-
Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
Substrates: -
Products: -
?
taxa-4,11-diene + [reduced NADPH-hemoprotein reductase] + O2
taxa-4(20),11-dien-5alpha-ol + [oxidized NADPH-hemoprotein reductase] + H2O
-
Substrates: reaction is completely dependent on NADPH, enzyme catalyzes the first oxygenating step in taxol biosynthesis pathway
Products: -
?
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cDNAs encoding taxa-4(5),11(12)-diene synthase and CYP725A4 are introduced in Nicotiana sylvestris for specific expression in trichome cells. Production of truncated TS in Escherichia coli. The TS cDNA coding for a protein truncated at the N-terminus at amino acid position 75 is cloned in the pET-30b expression vector. Furthermore, CYP725A4 is expressed in yeast.
CYP725A4, DNA and amino acid sequence determination and analysis, expression in the Saccharomyces cerevisiae WAT11 strain containing the Arabidopsis reductase ATR1, and co-expression in Nicotiana sylvestris with taxa-4(5),11(12)-diene synthase, which does not lead to 5alpha-hydroxytaxa-4(20),11(12)-diene, but to formation of 5(12)-oxa-3(11)-cyclotaxane, a tritiated oxidized taxane, structural analysis of the compound, phenotype, overview
expressed in Escherichia coli BL21 (DE3) cells
expressed in Escherichia coli BL21(DE3) cells
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expressed in Escherichia coli C41(DE3) cells
expressed in Saccharomyces cerevisiae and Escherichia coli
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drug development
paclitaxel is a successful anticancer drug
medicine
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enzyme may be useful in the biological production of the potent antimitotic drug taxol which shows activity against a range of cancers
medicine
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enzyme may be useful in the biological production of the potent antimitotic drug taxol which shows activity against a range of cancers
synthesis
engineered biosynthetic pathway for taxane production in Saccharomyces cerevisiae via chromosomal integration of Taxus cuspidata CYP725A4 and CPR genes. When expressed in the Saccharomyces cerevisiae strain, a potential T5alphaol isomer is the predominant product with maximum titers of 24 and 31 mg/l at micro and 1 l bioreactor scale, respectively. Total oxygenated taxane titers are improved to 78 mg/l and the acetylated acetylated T5alpha product is detected with a final titer of 3.7 mg/l
synthesis
expression of taxadiene synthase, taxadiene-5alpha-hydroxylase, and cytochrome P450 reductase in Nicotiana benthamiana. Using a chloroplastic compartmentalized metabolic engineering strategy and enhancement of isoprenoid precursors, the engineered plants can produce taxadiene and taxadiene-5alpha-ol at 56.6 microg/g fresh weight and 1.3 microg /g fresh weight, respectively
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Wheeler, A.L.; Long, R.M.; Ketchum, R.E.B.; Rithner, C.D.; Williams, R.M.; Croteau, R.
Taxol biosynthesis: differential transformations of taxadien-5alpha-ol and its acetate ester by cytochrome P450 hydroxylases from Taxus suspension cells
Arch. Biochem. Biophys.
390
265-278
2001
Taxus cuspidata
brenda
Hefner, J.; Rubenstein, S.M.; Ketchum, R.E.B.; Gibson, D.M.; Williams, R.M.; Croteau, R.
Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5alpha-ol: the first oxygenation step in taxol biosynthesis
Chem. Biol.
3
479-489
1996
Taxus brevifolia, Taxus cuspidata
brenda
Walker, K.; Croteau, R.
Taxol biosynthetic genes
Phytochemistry
58
1-7
2001
Taxus brevifolia, Taxus cuspidata
brenda
Jennewein, S.; Long, R.M.; Williams, R.M.; Croteau, R.
Cytochrome p450 taxadiene 5alpha-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of taxol biosynthesis
Chem. Biol.
11
379-387
2004
Taxus cuspidata (Q6WG30)
brenda
Rontein, D.; Onillon, S.; Herbette, G.; Lesot, A.; Werck-Reichhart, D.; Sallaud, C.; Tissier, A.
CYP725A4 from yew catalyzes complex structural rearrangement of taxa-4(5),11(12)-diene into the yclic ether 5(12)-oxa-3(11)-cyclotaxane
J. Biol. Chem.
283
6067-6075
2008
Taxus cuspidata (Q6WG30)
brenda
Biggs, B.W.; Rouck, J.E.; Kambalyal, A.; Arnold, W.; Lim, C.G.; De Mey, M.; ONeil-Johnson, M.; Starks, C.M.; Das, A.; Ajikumar, P.K.
Orthogonal assays clarify the oxidative biochemistry of taxol P450 CYP725A4
ACS Chem. Biol.
11
1445-1451
2016
Taxus brevifolia
brenda
Edgar, S.; Zhou, K.; Qiao, K.; King, J.R.; Simpson, J.H.; Stephanopoulos, G.
Mechanistic insights into taxadiene epoxidation by taxadiene-5alpha-hydroxylase
ACS Chem. Biol.
11
460-469
2016
Taxus cuspidata (Q6WG30)
brenda
Edgar, S.; Li, F.S.; Qiao, K.; Weng, J.K.; Stephanopoulos, G.
Engineering of taxadiene synthase for improved selectivity and yield of a key taxol biosynthetic intermediate
ACS Synth. Biol.
6
201-205
2017
Taxus sp.
brenda
Sagwan-Barkdoll, L.; Anterola, A.M.
Taxadiene-5alpha-ol is a minor product of CYP725A4 when expressed in Escherichia coli
Biotechnol. Appl. Biochem.
65
294-305
2018
Taxus cuspidata (Q6WG30), Taxus cuspidata
brenda
Rouck, J.E.; Biggs, B.W.; Kambalyal, A.; Arnold, W.R.; De Mey, M.; Ajikumar, P.K.; Das, A.
Heterologous expression and characterization of plant taxadiene-5alpha-hydroxylase (CYP725A4) in Escherichia coli
Protein Expr. Purif.
132
60-67
2017
Taxus cuspidata (Q6WG30)
brenda
Walls, L.E.; Malci, K.; Nowrouzi, B.; Li, R.; d'Espaux, L.; Wong, J.; Dennis, J.A.; Semiao, A.J.C.; Wallace, S.; Martinez, J.L.; Keasling, J.D.; Rios-Solis, L.
Optimising the biosynthesis of oxygenated and acetylated taxol precursors in Saccharomyces cerevisiae using advanced bioprocessing strategies
Biotechnol. Bioeng.
118
279-293
2020
Taxus cuspidata (Q6WG30)
brenda
Li, J.; Mutanda, I.; Wang, K.; Yang, L.; Wang, J.; Wang, Y.
Chloroplastic metabolic engineering coupled with isoprenoid pool enhancement for committed taxanes biosynthesis in Nicotiana benthamiana
Nat. Commun.
10
4850
2019
Taxus cuspidata (Q6WG30)
brenda