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Information on EC 4.2.3.17 - taxadiene synthase and Organism(s) Taxus brevifolia and UniProt Accession Q41594
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4.2.3.17 taxadiene synthaseIUBMB Comments
This is the committed step in the biosynthesis of the diterpenoid antineoplastic drug Taxol (paclitaxel). The cyclization involves a 1,5-hydride shift.
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Word Map
- 4.2.3.17
- taxus
- paclitaxel
-
taxane
- brevifolia
- tx
-
diterpene
-
diterpenoids
-
taxoids
-
carbocation
- medicine
-
10-deacetylbaccatin
- baccata
-
taxol-producing
- cuspidata
- mairei
- ggpps
- synthesis
- drug development
The taxonomic range for the selected organisms is: Taxus brevifolia
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
taxadiene synthase, taxa-4(5),11(12)-diene synthase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
geranylgeranyl pyrophosphate cyclase
-
-
-
-
taxa-4(5),11(12)-diene synthase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
cyclization
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -
SYSTEMATIC NAME
IUBMB Comments
geranylgeranyl-diphosphate diphosphate-lyase (cyclizing; taxa-4,11-diene-forming)
This is the committed step in the biosynthesis of the diterpenoid antineoplastic drug Taxol (paclitaxel). The cyclization involves a 1,5-hydride shift.
CAS REGISTRY NUMBER
COMMENTARY
169277-52-5
-
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
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
?
(10,11R)-dihydrogeranylgeranyl diphosphate
(1S,12R)-11,12-dihydroisocembrene + diphosphate
-
-
-
-
?
(10,11S)-dihydrogeranylgeranyl diphosphate
(1S,12S)-11,12-dihydroisocembrene + diphosphate
-
-
-
-
?
(2E,6E,10Z)-geranylgeranyl diphosphate
(1S,11,12Z)-isocembrene + diphosphate
-
-
-
-
?
(E,E,E)-geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
first committed step of taxol biosynthesis
-
-
?
(E,E,E)-geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
mechanism of cyclization. Incubation of (R)-[4-2H1]geranylgeranyl diphosphate gives a 10:10:80 mixture of [5beta-2H1]taxa-3(4),11(12)-diens, [5beta-2H1]taxa-4(20),11(12)-diene and unlabeled taxa-4(5),11(12)-diene
-
-
?
11-desmethylgeranylgeranyl diphosphate
(1S)-12-desmethylisocembrene + diphosphate
-
-
-
-
?
7-fluorogeranylgeranyl diphosphate
(1R,3E,7Z,11R)-7-fluoro-4,8,12,15,15-pentamethyl-bicyclo[9.3.1]pentadeca-3,7,12-triene
-
-
i.e. endo-7-fluoroverticillene, 25% yield
-
?
7-fluorogeranylgeranyl diphosphate
(1S,3E,7Z,11R)-7-fluoro-4,8,15,15-tetramethyl-12-methylene-bicyclo[9.3.1]pentadeca-3,7-diene
-
verticille-12-yl carbocation intermediate with an 11R stereocenter, the reaction gives three main products and two further isomers
i.e. exo-7-fluoroverticillene, 37% yield
-
?
7-fluorogeranylgeranyl diphosphate
4(20)-methylene-7-fluoroverticillene
-
-
i.e. 4(20)-methylene-7-fluoroverticillene, 26% yield
-
?
geranylgeranyl diphosphate
taxa-4(20),11(12)-diene + diphosphate
-
taxa-4(20),11(12)-diene is formed as a small amount
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
isocembrenyl cation is possibly an intermediate in the cyclization of geranylgeranyl diphosphate to taxadiene
-
-
?
additional information
?
-
-
the wild-type enzyme forms cembrene A as a side product, while enzyme mutant W753H produces cembrene A as main product
-
-
?
additional information
?
-
the wild-type enzyme forms cembrene A as a side product, while enzyme mutant W753H produces cembrene A as main product
-
-
?
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
(E,E,E)-geranylgeranyl diphosphate
taxa-4(5),11(12)-diene + diphosphate
-
first committed step of taxol biosynthesis
-
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
-
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
geranylgeranyl diphosphate
taxa-4,11-diene + diphosphate
-
catalyzes the first step in taxol biosynthesis
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.003
geranylgeranyl diphosphate
-
pH and temperature not specified in the publication
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0106
geranylgeranyl diphosphate
-
pH and temperature not specified in the publication
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3.5
geranylgeranyl diphosphate
-
pH and temperature not specified in the publication
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
key enzyme in directing pathway flux toward taxol precursors, such as taxadien-5alpha-ol
additional information
additional information
-
detailed mechanistic analysis of the biosynthesis of taxadiene by enzyme TXS using a hybrid quantum mechanics-molecular mechanics potential in conjunction with free energy simulation methods, overview. Generation of a free-energy fingerprint for type I terpene synthases. The active-site Trp residue W753 is a key feature of the TXS active-site architecture and stabilizes intermediate cations via Pi-cation interactions
additional information
detailed mechanistic analysis of the biosynthesis of taxadiene by enzyme TXS using a hybrid quantum mechanics-molecular mechanics potential in conjunction with free energy simulation methods, overview. Generation of a free-energy fingerprint for type I terpene synthases. The active-site Trp residue W753 is a key feature of the TXS active-site architecture and stabilizes intermediate cations via Pi-cation interactions
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). TASY_TAXBR
862
0
98304
Swiss-Prot
Chloroplast (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
X-ray crystal structure of a truncation variant lacking the transit sequence and an additional 27 residues at the N-terminus, complexed with 13-aza-13,14-dihydrocopalyl diphosphate, at 1.82 A resolution, and 2-fluorogeranylgeranyl diphosphate, at 2.25 A resolution. The structure reveals a modular assembly of three alpha-helical domains. The C-terminal catalytic domain is a class I terpenoid cyclase, which binds and activates substrate GGPP with a three-metal ion cluster. The N-terminal domain and a third insertion domain together adopt the fold of a vestigial class II terpenoid cyclase
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
W753H
the mutation leads to the exclusive formation of side product cembrene A. The simulations of the W753H mutant shows that, in the mutant structure, the His side chain is in the perfect position to deprotonate the cembrenyl cation en route to cembrene formation and that this abortive deprotonation is an energetically facile process
W753H
the mutation leads to the exclusive formation of side product cembrene A
additional information
additional information
construction of truncation variant lacking the transit sequence and an additional 27 residues at the N-terminus, crystallization data
additional information
-
construction of truncation variant lacking the transit sequence and an additional 27 residues at the N-terminus, crystallization data
additional information
-
a mutation Y841H, analogous to W753H mutation, can possibly lead to formation of verticillane
additional information
a mutation Y841H, analogous to W753H mutation, can possibly lead to formation of verticillane
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
chemotherapeutic agent against a range of cancers, including ovarian and breast cancer
synthesis
medicine
-
chemotherapeutic agent against a range of cancers, including ovarian and breast cancer
synthesis
-
taxadiene synthase ist he rate-limiting enzyme in the biosynthesis of the anticancer compound paclitaxel
synthesis
constitutive expression in Nicotiana benthamiana leads to de novo production of taxadiene. Transformed homozygous lines produce 11-27 microg taxadiene/g of dry weight. Treatment with an elicitor, methyl jasmonate, and metabolic pathway shunting by suppression of the phytoene synthase gene expression results in increased taxadiene accumulation by 1.4- or 1.9fold, respectively
synthesis
transformation of the roots of cultured Panax ginseng C.A. Meyer to produce taxadiene. Without any change in phenotypes or growth difference, a taxadiene synthase-transgenic ginseng line accumulates 9.1 microg taxadiene per gram of dry weight. In response to the treatment of methyl jasmonate for 3 or 6 days, the accumulation is 14.6 and 15.9 microg per g of dry weight, respectively
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hezari, M.; Ketchum, R.E.B.; Gibson, D.M.; Croteau, R.
Taxol production and taxadiene synthase activity in Taxus canadensis cell suspension cultures
Arch. Biochem. Biophys.
337
185-190
1997
Taxus brevifolia, Taxus canadensis
Wildung, M.R.; Croteau, R.
A cDNA clone for taxadiene synthase, the diterpene cyclase that catalyzes the committed step of taxol biosynthesis
J. Biol. Chem.
271
9201-9204
1996
Taxus brevifolia (Q41594), Taxus brevifolia
Koepp, A.E.; Hezari, M.; Zajicek, J.; Stofer Vogel, B.; LaFever, R.; Lewis, N.G.; Croteau, R.
Cyclization of geranylgeranyl diphosphateto taxa-4(5),-11(12)-diene is the comitted step of taxol biosynthesis in pacific yew
J. Biol. Chem.
270
8686-8690
1995
Taxus brevifolia
Lin, X.; Hezari, M.; Koepp, A.E.; Floss, H.G.; Croteau, R.
Mechanism of taxadiene synthase, a diterpene cyclase that catalyzes the first step of taxol biosynthesis in pacific yew
Biochemistry
35
2968-2977
1996
Taxus brevifolia
Williams, D.C.; Carroll, B.J.; Jin, Q.; Rithner, C.D.; Lenger, S.R.; Floss, H.G.; Coates, R.M.; Williams, R.M.; Croteau, R.
Intramolecular proton transfer in the cyclization of geranylgeranyl diphosphate to the taxadiene precursor of taxol catalyzed by recombinant taxadiene synthase
Chem. Biol.
7
969-977
2000
Taxus brevifolia
Williams, D.C.; Wildung, M.R.; Jin, A.Q.; Dalal, D.; Oliver, J.S.; Coates, R.M.; Croteau, R.
Heterologous xpression and characterization of a "Pseudomature" form of taxadiene synthase involved in paclitaxel (taxol) biosynthesis and evaluation of a potential intermediate and inhibitors of the multistep diterpene cyclization reaction
Arch. Biochem. Biophys.
379
137-146
2000
Taxus brevifolia
Huang, Q.; Roessner, C.A.; Croteau, R.; Scott, A.I.
Engineering Escherichia coli for the synthesis of taxadiene, a key intermediate in the biosynthesis of taxol
Bioorg. Med. Chem.
9
2237-2242
2001
Taxus brevifolia
Huang, Q.; Williams, H.J.; Roessner, C.A.; Scott, A.I.
Sesquiterpenes produced by truncated taxadiene synthase
Tetrahedron Lett.
41
9701-9704
2000
Taxus brevifolia
-
Jin, Y.; Williams, D.C.; Croteau, R.; Coates, R.M.
Taxadiene synthase-catalyzed cyclization of 6-fluorogeranylgeranyl diphosphate to 7-fluoroverticillenes
J. Am. Chem. Soc.
127
7834-7842
2005
Taxus brevifolia
Jin, Q.; Williams, D.C.; Hezari, M.; Croteau, R.; Coates, R.M.
Stereochemistry of the macrocyclization and elimination steps in taxadiene biosynthesis through deuterium labeling
J. Org. Chem.
70
4667-4675
2005
Taxus brevifolia
Chow, S.Y.; Williams, H.J.; Huang, Q.; Nanda, S.; Scott, A.I.
Studies on taxadiene synthase: interception of the cyclization cascade at the isocembrene stage with GGPP analogues
J. Org. Chem.
70
9997-10003
2005
Taxus brevifolia
Anterola, A.; Shanle, E.; Perroud, P.F.; Quatrano, R.
Production of taxa-4(5),11(12)-diene by transgenic Physcomitrella patens
Transgenic Res.
18
655-660
2009
Taxus brevifolia
Koeksal, M.; Jin, Y.; Coates, R.M.; Croteau, R.; Christianson, D.W.
Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis
Nature
469
116-120
2011
Taxus brevifolia (Q41594), Taxus brevifolia
Cha, M.; Shim, S.H.; Kim, S.H.; Kim, O.T.; Lee, S.W.; Kwon, S.Y.; Baek, K.H.
Production of taxadiene from cultured ginseng roots transformed with taxadiene synthase gene
BMB Rep.
45
589-594
2012
Taxus brevifolia (Q41594), Taxus brevifolia
Hasan, M.M.; Kim, H.S.; Jeon, J.H.; Kim, S.H.; Moon, B.; Song, J.Y.; Shim, S.H.; Baek, K.H.
Metabolic engineering of Nicotiana benthamiana for the increased production of taxadiene
Plant Cell Rep.
33
895-904
2014
Taxus brevifolia (Q41594), Taxus brevifolia
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 brevifolia (Q41594)
Freud, Y.; Ansbacher, T.; Major, D.
Catalytic control in the facile proton transfer in taxadiene synthase
ACS Catal.
7
7653-7657
2017
Taxus brevifolia (Q41594)
-
Pemberton, T.A.; Chen, M.; Harris, G.G.; Chou, W.K.; Duan, L.; Koeksal, M.; Genshaft, A.S.; Cane, D.E.; Christianson, D.W.
Exploring the influence of domain architecture on the catalytic function of diterpene synthases
Biochemistry
56
2010-2023
2017
Taxus brevifolia
Ansbacher, T.; Freud, Y.; Major, D.
Slow-starter enzymes role of active-site architecture in the catalytic control of the biosynthesis of taxadiene by taxadiene synthase
Biochemistry
57
3773-3779
2018
Taxus brevifolia, Taxus brevifolia (Q41594)
Li, M.; Jiang, F.; Yu, X.; Miao, Z.
Engineering isoprenoid biosynthesis in Artemisia annua L. for the production of taxadiene a key intermediate of taxol
BioMed Res. Int.
2015
504932
2015
Taxus brevifolia (Q41594)
Soliman, S.; Tang, Y.
Natural and engineered production of taxadiene with taxadiene synthase
Biotechnol. Bioeng.
112
229-235
2015
Taxus brevifolia
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