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Information on EC 4.2.3.175 - 10-epi-cubebol synthase
for references in articles please use BRENDA:EC4.2.3.175
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EC Tree 4 Lyases
4.2 Carbon-oxygen lyases
4.2.3 Acting on phosphates
4.2.3.175 10-epi-cubebol synthase
IUBMB Comments
Isolated from the bacterium Sorangium cellulosum So ce56. The enzyme is also responsible for the formation of trace amounts of many other sesquiterpenes, mainly cadinanes and cubebanes.
The expected taxonomic range for this enzyme is: Sorangium cellulosum
showSynonyms
sce6369, 10-epi-cubebol synthase, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
class I 10-epi-cubebol synthase
CubS
ScCubS
sce6369
sce6369
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-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(2E,6E)-farnesyl diphosphate + H2O = 10-epi-cubebol + diphosphate
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-
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(2E,6E)-farnesyl diphosphate + H2O = 10-epi-cubebol + diphosphate
proposed mechanism for the formation of 10-epi-cubebol and key side products from FPP by ScCubS, reaction mechanism via carbocation, the product is derived from the germacrane scaffold. Detailed reaction mechansim analysis, overview
(2E,6E)-farnesyl diphosphate + H2O = 10-epi-cubebol + diphosphate
proposed mechanism for the formation of 10-epi-cubebol and key side products from FPP by ScCubS, reaction mechanism via carbocation, the product is derived from the germacrane scaffold. Detailed reaction mechansim analysis, overview
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SYSTEMATIC NAME
IUBMB Comments
(2E,6E)-farnesyl-diphosphate diphosphate-lyase (cyclizing, 10-epi-cubebol-forming)
Isolated from the bacterium Sorangium cellulosum So ce56. The enzyme is also responsible for the formation of trace amounts of many other sesquiterpenes, mainly cadinanes and cubebanes.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(2E,6E)-farnesyl diphosphate + H2O
10-epi-cubebol + diphosphate
Substrates: -
Products: -
Products: -
?
(2E,6E)-farnesyl diphosphate + H2O
10-epi-cubebol + diphosphate
Substrates: -
Products: -
Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(2E,6E)-farnesyl diphosphate + H2O
10-epi-cubebol + diphosphate
Substrates: -
Products: -
Products: -
?
(2E,6E)-farnesyl diphosphate + H2O
10-epi-cubebol + diphosphate
Substrates: -
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
Mg2+
required, trinuclear Mg2+ cluster and metal-binding motif analysis
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
physiological function
additional information
metabolism
residues N327 and F104 drive the substrate beyond the germacrane scaffold and open up the cadalane scaffolds by unlocking the second intramolecular cyclization. S206 and F211 then unlock the third cyclization which achieves cubebanes, including 10-epi-cubebol
metabolism
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residues N327 and F104 drive the substrate beyond the germacrane scaffold and open up the cadalane scaffolds by unlocking the second intramolecular cyclization. S206 and F211 then unlock the third cyclization which achieves cubebanes, including 10-epi-cubebol
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physiological function
feeding mevalonolactone to a sce6369 expressing Escherichia coli strain results in a mixture of 21 sesquiterpene products. Structurally identified sesquiterpenes have all cadalane- and cubebane-type scaffolds with the exception of germacrene D. Main product is 10-epi-cubebol
physiological function
class I 10-epi-cubebol synthase (ScCubS) is responsible for most of the sesquiterpenoids observed in the volatile extract of Sorangium cellulosum strain So ce56.23. ScCubS is capable of making over 20 different sesquiterpenoids when expressed in a heterologous Escherichia coli host, the majority of which are derived from the germacrane, cubebane, and cadalane hydrocarbon skeletons. Wild-type ScCubS generates 10-epi-cubebol at high purity, representing around 90% of all of the sesquiterpenoids produced. The other sesquiterpenoids detected are cis-muurola-3,5-diene, (E)-beta-farnesene, germacrene D, cubebol, germacradien-4-ol, gamma-cadinene, and five unidentified sesquiterpenes
physiological function
-
feeding mevalonolactone to a sce6369 expressing Escherichia coli strain results in a mixture of 21 sesquiterpene products. Structurally identified sesquiterpenes have all cadalane- and cubebane-type scaffolds with the exception of germacrene D. Main product is 10-epi-cubebol
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physiological function
-
class I 10-epi-cubebol synthase (ScCubS) is responsible for most of the sesquiterpenoids observed in the volatile extract of Sorangium cellulosum strain So ce56.23. ScCubS is capable of making over 20 different sesquiterpenoids when expressed in a heterologous Escherichia coli host, the majority of which are derived from the germacrane, cubebane, and cadalane hydrocarbon skeletons. Wild-type ScCubS generates 10-epi-cubebol at high purity, representing around 90% of all of the sesquiterpenoids produced. The other sesquiterpenoids detected are cis-muurola-3,5-diene, (E)-beta-farnesene, germacrene D, cubebol, germacradien-4-ol, gamma-cadinene, and five unidentified sesquiterpenes
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additional information
10-epi-cubebol synthase from Sorangium cellulosum (ScCubS) guides a highly reactive carbocationic substrate through the pathway, preventing early quenching and ensuring correct stereochemistry at every stage. The cyclizations carried out by ScCubS potentially represent significant evolutionary expansions in the chemical space accessible by TSs. Residue S206 is crucial in 10-epi-cubebol synthesis, and residues N327 and F104 control the distribution between several early-stage cations and whether the final product is derived from the germacrane, cadalane, or cubebane hydrocarbon scaffold. The main product is germacradien-4-ol, which derives from the germacrane, rather than the cubebane, scaffold. Residue F211 unlocks the third and final cyclization of the enzyme's reaction scheme
additional information
-
10-epi-cubebol synthase from Sorangium cellulosum (ScCubS) guides a highly reactive carbocationic substrate through the pathway, preventing early quenching and ensuring correct stereochemistry at every stage. The cyclizations carried out by ScCubS potentially represent significant evolutionary expansions in the chemical space accessible by TSs. Residue S206 is crucial in 10-epi-cubebol synthesis, and residues N327 and F104 control the distribution between several early-stage cations and whether the final product is derived from the germacrane, cadalane, or cubebane hydrocarbon scaffold. The main product is germacradien-4-ol, which derives from the germacrane, rather than the cubebane, scaffold. Residue F211 unlocks the third and final cyclization of the enzyme's reaction scheme
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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). ECUBS_SORC5
Sorangium cellulosum (strain So ce56)
315
0
36142
Swiss-Prot
Secretory Pathway (Reliability: 1)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
additional information
additional information
crystal structure and docking models of ScCubS and ScCubS-Mg32+-PPi crystal homodimer
additional information
-
crystal structure and docking models of ScCubS and ScCubS-Mg32+-PPi crystal homodimer
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant ScCubS in complex with both a trinuclear magnesium cluster and diphosphate (ScCubS-Mg_32+-PPi complex), X-ray diffraction structure determination and analysis at 1.8 A resolution
structure of CubS in complex with both a trinuclear magnesium cluster and diphosphate, to 1.80 A resolution. Residue S206 is crucial in 10-epi-cubebol synthesis by enlisting the nearby F211 to shape the active site contour and prevent the formation of early escape cadalane products. Residues N327 and F104 control the distribution between several early-stage cations and whether the final product is derived from the germacrane, cadalane, or cubebane hydrocarbon scaffold
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F104A
produces trace amounts of cyclic sesquiterpenes, not including 10-epi-cubebol
F104Y
produces 10-epicubebol at 1.23 mg/l and germacradien-4-ol at 7.59 mg/L, representing about 80% of all sesquiterpenes detected
F211A
F211L/N327D
F211W
F211W/N327D
F211Y
N327A
N327D
N327D/F211L
site-directed mutagenesis, the multiple change to the active site is tolerated poorly by the enzyme
N327D/F211W
site-directed mutagenesis, the multiple change to the active site is tolerated poorly by the enzyme
F104A
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produces trace amounts of cyclic sesquiterpenes, not including 10-epi-cubebol
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F211W/N327D
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produces only trace amounts of sesquiterpenes, germacradien-4-ol is the most abundant product
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N327A
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mutant produces main product 10-epi-cubebol (56% of total products) and germacradien-4-ol (44%), total sesquiterpene titer is around 0.4 mg/l
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N327D
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mutant produces main product 10-epi-cubebol at 55% and germacradien-4-ol at 30% of the total sesquiterpene titer, which is about 10.0 mg/l
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F211A
major product is 1,10-di-epi-cubenol, plus gamma-cadinene, and tau-cadinol
F211A
site-directed mutagenesis, for the mutant, the cubebane 10-epi-cubebol is replaced as the major product by the cadalane 1,10-di-epi-cubenol derived from cation D
F211W
site-directed mutagenesis, the mutant delivers 10-epi-cubebol as the main product at yields of 11.59 mg/l. The mutant can presumably stabilize C6/C7 and block quenching, albeit less well than phenylalanine
F211W/N327D
produces only trace amounts of sesquiterpenes, germacradien-4-ol is the most abundant product
F211W/N327D
site-directed mutagenesis, the mutant produces only trace amounts of sesquiterpenes
F211Y
site-directed mutagenesis, the mutant delivers 10-epi-cubebol as the main product at yields of 4.77 mg/l. The mutant can presumably stabilize C6/C7 and block quenching, albeit less well than phenylalanine
N327A
mutant produces main product 10-epi-cubebol (56% of total products) and germacradien-4-ol (44%), total sesquiterpene titer is around 0.4 mg/l
N327A
site-directed mutagenesis, only two products are detected: the main product 10-epi-cubebol (56% of total products) and germacradien-4-ol (Gd4ol, 44%), although the total sesquiterpene titer is a meager, suggesting N327 is more fundamentally important to the overall mechanism
N327D
mutant produces main product 10-epi-cubebol at 55% and germacradien-4-ol at 30% of the total sesquiterpene titer, which is about 10.0 mg/l
N327D
site-directed mutagenesis, only two products are detected: the main product 10-epi-cubebol (56% of total products) and germacradien-4-ol (Gd4ol, 44%), with a higher total sesquiterpene titer compared to mutant N327A
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of wild-type and mutant enzymes from Escherichia coli
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene sce6369, recombinant expression of wild-type and mutant enzymes in Escherichia coli
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Schifrin, A.; Khatri, Y.; Kirsch, P.; Thiel, V.; Schulz, S.; Bernhardt, R.
A single terpene synthase is responsible for a wide variety of sesquiterpenes in Sorangium cellulosum Soce56
Org. Biomol. Chem.
14
3385-3393
2016
Sorangium cellulosum (A9GK58), Sorangium cellulosum So ce56 (A9GK58), Sorangium cellulosum So ce56
brenda
Whitehead, J.N.; Leferink, N.G.H.; Komati Reddy, G.; Levy, C.W.; Hay, S.; Takano, E.; Scrutton, N.S.
How a 10-epi-cubebol synthase avoids premature reaction quenching to form a tricyclic product at high purity
ACS Catal.
12
12123-12131
2022
Sorangium cellulosum (A9GK58), Sorangium cellulosum So ce56 (A9GK58)
brenda
EXTERNAL LINKS (specific for EC-Number 4.2.3.175)
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Release 2026.1 (March 2026)
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