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Information on EC 5.5.1.8 - (+)-bornyl diphosphate synthase and Organism(s) Salvia officinalis and UniProt Accession O81192
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5.5.1.8 (+)-bornyl diphosphate synthaseIUBMB Comments
Requires Mg2+. The enzyme from Salvia officinalis (sage) can also use (3R)-linalyl diphosphate or more slowly neryl diphosphate in vitro . The reaction proceeds via isomeration of geranyl diphosphate to (3R)-linalyl diphosphate. The oxygen and phosphorus originally linked to C-1 of geranyl diphosphate end up linked to C-2 of (+)-bornyl diphosphate . cf. EC 5.5.1.22 [(-)-bornyl diphosphate synthase].
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Word Map
The taxonomic range for the selected organisms is: Salvia officinalis
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
bornyl diphosphate synthase, (+)-bornyl diphosphate synthase, (di)terpene synthase, geranyl pyrophosphate:(+)-bornyl pyrophosphate cyclase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
(+)-Bornylpyrophosphate cyclase
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(+)-BPP cyclase
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(-)-BPP cyclase
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bornyl pyrophosphate synthase
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bornyl pyrophosphate synthetase
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Geranyl pyrophosphate:(+)-bornyl pyrophosphate cyclase
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Geranyl pyrophosphate:(-)-bornyl pyrophosphate cyclase
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geranyl-diphosphate cyclase
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Synthetase, bornyl pyrophosphate
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
geranyl diphosphate = (+)-bornyl diphosphate
geranyl diphosphate is first stereospecifically isomerized to linalyl diphosphate which, following rotation about C-2-B-3 to the cisoid conformer, cyclizes from the anti-endo configuration. Neryl diphosphate cyclizes either directly or via the linalyl intermediate without the attendant rotation
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geranyl diphosphate = (+)-bornyl diphosphate
linalyl diphosphate is an intermediate
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geranyl diphosphate = (+)-bornyl diphosphate
solely the diphosphate ester oxygen of geranyl diphosphate is involved in all the critical bonding processes in the coupled isomerization-cyclization
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geranyl diphosphate = (+)-bornyl diphosphate
both steps of the coupled isomerization-cyclization sequence are initiated by ionization of an allylic diphosphate
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geranyl diphosphate = (+)-bornyl diphosphate
reaction mechanism, overview
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PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -
SYSTEMATIC NAME
IUBMB Comments
(+)-bornyl-diphosphate lyase (decyclizing)
Requires Mg2+. The enzyme from Salvia officinalis (sage) can also use (3R)-linalyl diphosphate or more slowly neryl diphosphate in vitro [3]. The reaction proceeds via isomeration of geranyl diphosphate to (3R)-linalyl diphosphate. The oxygen and phosphorus originally linked to C-1 of geranyl diphosphate end up linked to C-2 of (+)-bornyl diphosphate [3]. cf. EC 5.5.1.22 [(-)-bornyl diphosphate synthase].
CAS REGISTRY NUMBER
COMMENTARY
72668-91-8
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Geranyl diphosphate
?
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formation of bornyl diphosphate is the rate-limiting step in camphor biosynthesis even in immature leaf tissue
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?
geranyl diphosphate
(+)-bornyl diphosphate
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the enzyme is involved in monoterpenoid cyclase catalysis, mechanism of this coupled isomerization-cyclization reaction, modeling, overview
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?
geranyl diphosphate
(+)-bornyl diphosphate
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bornyl diphosphate synthase is an unusual example of a monoterpene synthase, because the diphosphate leaving group of the geranyl substrate is recaptured in the final product
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?
Geranyl diphosphate
(+)-Bornyl-diphosphate
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(+)-(1R,4R)-bornyl-diphosphate
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Geranyl diphosphate
(+)-Bornyl-diphosphate
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geranyl diphosphate is preferred over neryl diphosphate
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?
Neryl diphosphate
(+)-Bornyl-diphosphate
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(+)-(1R,4R)-bornyl diphosphate
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Neryl diphosphate
(+)-Bornyl-diphosphate
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geranyl diphosphate is preferred over neryl diphosphate
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?
additional information
?
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the C-terminal domain catalyzes the cyclization of geranyl diphosphate, orienting and stabilizing multiple reactive carbocation intermediates. The N-terminal domain has no clearly defined function, although its N-terminus caps the active site in the C-terminal domain during catalysis
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?
additional information
?
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the C-terminal domain catalyzes the cyclization of geranyl diphosphate, orienting and stabilizing multiple reactive carbocation intermediates. The N-terminal domain has no clearly defined function, although its N-terminus caps the active site in the C-terminal domain during catalysis
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?
additional information
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the reaction mechanism in BPPS involves the following steps: binding of geranyl diphospahte, metal-activated ionization to yield an allylic transoid carbocation, formation of (3R)-linalyl diphosphate, rotation around the C2-C3 bond and ionization to generate a cisoid allylic cation in the reactive conformation, cyclization to form a (4R)-R-terpinyl cation, further cyclization to yield (+)-2-bornyl cation, and reincorporation of the diphosphate by the (+)-2-bornyl carbocation, to yield the final product (+)-bornyl diphosphate in ca. 75% yield
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?
additional information
?
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(di)terpene synthases seem to mediate specific reaction outcomes, at least in part, by providing electrostatic effects to counteract those exerted by the diphosphate co-product. Role for the diphosphate anion co-product in the reaction catalyzed by monoterpene cyclases, such as bornyl diphosphate synthase
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?
additional information
?
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hydroxyl dipole stabilization of the specific carbocation formed by initial cyclization, enabling deprotonation of this early intermediate, whereas the lack of such stabilization, i.e. in the presence of an aliphatic side chain leads to carbocation migration towards the pyrophosphate co-product, resulting in a more complex reaction. The 7-aza-7,8-dihydrolimonene analogue is clearly bound backwards to enable aza-diphosphate ion-pairing, indicating that this is the thermodynamically favored binding mode for such a carbocation. The diphosphate co-product is tightly bound and may serve as a general acid/base during terpene synthase reactions without becoming reattached itself. Consistent with such tight binding is the stereospecificity of bornyl diphosphate formation by BPS, which reattaches the bornyl cation to the same oxygen of the diphosphate involved in the original diphosphate ester bond of the GPP substrate, indicating that the diphosphate anion remains in a fixed orientation during the catalyzed reaction
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Geranyl diphosphate
?
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formation of bornyl diphosphate is the rate-limiting step in camphor biosynthesis even in immature leaf tissue
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?
additional information
?
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(di)terpene synthases seem to mediate specific reaction outcomes, at least in part, by providing electrostatic effects to counteract those exerted by the diphosphate co-product. Role for the diphosphate anion co-product in the reaction catalyzed by monoterpene cyclases, such as bornyl diphosphate synthase
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?
geranyl diphosphate
(+)-bornyl diphosphate
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the enzyme is involved in monoterpenoid cyclase catalysis, mechanism of this coupled isomerization-cyclization reaction, modeling, overview
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?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(3R)-homolinalyl diphosphate
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i.e. 2,6-dimethyl-2-vinyl-5-heptenyl diphosphate
(3S)-homolinalyl diphosphate
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i.e. 2,6-dimethyl-2-vinyl-5-heptenyl diphosphate
3-aza-2,3-dihydrogeranyl diphosphate
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competitive inhibition, the aza-analog of the substrate is bound anomalously, perhaps as a consequence of the positive charge, bond distortion, or hydrogen bonding resulting from the N for C substitution, binding strutcure, overview
6-cyclopropylidene-(3E)-methyl-hex-2-en-1-yl diphosphate
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about 50% inhibition at 0.01 mM for 20 min
linalyl diphosphate
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competitive inhibition, the enantioselective synthase readily distinguishes between (3R)- and (3S)-homolinalyl diphosphates, both of which were more effective inhibitors than is 3-azageranyl diphosphate, the fluorinated analogues prove to be the most potent competitive inhibitors
Methyl-(4-methylpent-3-en-1-yl)vinyl sulfonium perchlorate
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potency of inhibition increases with increasing substrate concentration. A combination of sulfonium analog and 0.05 mM diphosphate provides synergistic inhibition
Dimethyl-(4-methylcyclohex-3-en-1-yl)sulfonium iodide
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potency of inhibition increases with increasing substrate concentration. A combination of sulfonium analog and 0.05 mM diphosphate provides synergistic inhibition
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.2
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geranyl diphosphate and neryl diphosphate, the maximal activity with geranyl diphosphate is about 5times higher than with neryl diphosphate
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.7 - 6.7
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pH 5.7: about 40% of maximal activity, pH 6.7: about 35% of maximal activity, geranyl diphosphate
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
especially in young leaves, expression pattern analysis, overview
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
bornyl diphosphate synthase is responsible for the first step in camphor biosynthesis producing bornyl diphosphate, which is subsequently hydrolyzed to borneol and then oxidized to camphor, pathway overview
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). BPPS_SALOF
598
0
69292
Swiss-Prot
Chloroplast (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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analysis of tertiary crystal structures of bornyl diphosphate synthase, the aza moiety is ion-paired with the diphosphate, whose position is essentially invariant
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging-drop vapor-diffusion method, structure of complexes with aza analogues of substrate and carbocation intermediates, as well as complexes with diphosphate and bornyl diphosphate, determined at 2.0 A resolution
analysis of tertiary crystal structures of bornyl diphosphate synthase complexed with diphosphate and/or aza-analogs, mimicking various carbocations of the BPS catalyzed reaction
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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the recombinant enzyme is similarly truncated at E50 to provide a pseudomature form devoid of the plastid transit peptide
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
mechanized techniques for the selective extraction of enzymes from plant epidermal glands
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
the enzyme is induced by gibberellic acids I and II in leaves, especially in young leaves
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lanznaster, N.; Croteau, R.
Dye-ligand immobilized metal ion interaction chromatography for the purification of enzymes of prenyl pyrophosphate metabolism
Protein Expr. Purif.
2
69-74
1991
Salvia officinalis
Wheeler, C.J.; Mihaliak, C.A.; Croteau, R.
Uncompetitive inhibition of monoterpene cyclases by an analog of the substrate geranyl pyrophosphate and inhibition of monoterpene biosynthesis in vivo by an analog of geraniol
Arch. Biochem. Biophys.
279
303-210
1990
Salvia officinalis
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Cane, D.E.; Saito, A.; Croteau, R.; Shaskus, J.; Felton, M.
Enzymatic cyclization of geranyl pyrophosphate to bornyl pyrophosphate. Role of the pyrophosphate moiety
J. Am. Chem. Soc.
104
5831-5833
1982
Salvia officinalis
-
Croteau, R.B.; Shaskus, J.J.; Renstrom, B.; Felton, N.M.; Cane, D.E.; Saito, A.; Chang, C.
Mechanism of the pyrophosphate migration in the enzymatic cyclization of geranyl and linalyl pyrophosphate to (+)- and (-)-bornyl pyrophosphate
Biochemistry
24
7077-7085
1985
Salvia officinalis, Tanacetum vulgare
Croteau, R.; Karp, F.
Biosynthesis of monoterpenes: preliminary characterization of bornyl pyrophosphate synthetase from sage (Salvia officinalis) and demonstration that geranyl pyrophosphate is the preferred substrate for cyclization
Arch. Biochem. Biophys.
198
512-522
1979
Salvia officinalis
Croteau, R.; Alonso, W.R.; Koepp, A.E.; Shim, J.H.; Cane, D.E.
Irreversible inactivation of monoterpene cyclases by a mechanism-based inhibitor
Arch. Biochem. Biophys.
307
397-404
1993
Salvia officinalis, Tanacetum vulgare
Croteau, R.; Felton, M.; Karp, F.; Kjonaas, R.
Relationship of camphor biosynthesis to leaf development in sage (Salvia officinalis)
Plant Physiol.
67
820-824
1981
Salvia officinalis
Croteau, R.; Felton, N.M.; Wheeler, C.J.
Stereochemistry at C-1 of geranyl pyrophosphate and neryl pyrophosphate in the cyclization to (+)- and (-)-bornyl pyrophosphate
J. Biol. Chem.
260
5956-5962
1985
Salvia officinalis, Tanacetum vulgare
Wheeler, C.J.; Croteau, R.
Monoterpene cyclases: use of the noncyclizable substrate analog 6,7-dihydrogeranyl pyrophosphate to uncouple the isomerization step of the coupled isomerization-cyclization reaction
Arch. Biochem. Biophys.
246
733-742
1986
Salvia officinalis
Croteau, R.; Wheeler, C.J.; Aksela, R.; Oehlschlager, A.C.
Inhibition of monoterpene cyclases by sulfonium analogs of presumptive carbocationic intermediates of the cyclization reaction
J. Biol. Chem.
261
7257-7263
1986
Salvia officinalis
Croteau, R.; Satterwhite, D.M.; Cane, D.E.; Chang, C.C.
Biosynthesis of monoterpenes. Enantioselectivity in the enzymatic cyclization of (+)- and (-)-linalyl pyrophosphate to (+)- and (-)-bornyl pyrophosphate
J. Biol. Chem.
261
13438-13445
1986
Salvia officinalis, Tanacetum vulgare
Croteau, R.
Evidence for the ionization steps in monoterpene cyclization reactions using 2-fluorogeranyl and 2-fluorolinalyl pyrophosphates as substrates
Arch. Biochem. Biophys.
251
777-782
1986
Salvia officinalis
Wheeler, C.J.; Croteau, R.
Monoterpene cyclases. Stereoelectronic requirements for substrate binding and ionization
J. Biol. Chem.
262
8213-8219
1987
Salvia officinalis
Gershenzon, J.; Duffy, M.A.; Karp, F.; Croteau, R.
Mechanized techniques for the selective extraction of enzymes from plant epidermal glands
Anal. Biochem.
163
159-164
1987
Salvia officinalis, Tanacetum vulgare
Wheeler, C.J.; Croteau, R.
Monoterpene cyclases: physicochemical features required for pyrophosphate binding determined from inhibition by structural analogs
Arch. Biochem. Biophys.
260
250-256
1988
Salvia officinalis
Wise, M.L.; Savage, T.J.; Katahira, E.; Croteau, R.
Monoterpene synthases from common sage (Salvia officinalis). cDNA isolation, characterization, and functional expression of (+)-sabinene synthase, 1,8-cineole synthase, and (+)-bornyl diphosphate synthase
J. Biol. Chem.
273
14891-14899
1998
Salvia officinalis (O81192)
Whittington, D.A.; Wise, M.L.; Urbansky, M.; Coates, R.M.; Croteau, R.B.; Christianson, D.W.
Bornyl diphosphate synthase: structure and strategy for carbocation manipulation by a terpenoid cyclase
Proc. Natl. Acad. Sci. USA
99
15375-15380
2002
Salvia officinalis (O81192), Salvia officinalis
Karp, F.; Zhao, Y.; Santhamma, B.; Assink, B.; Coates, R.M.; Croteau, R.B.
Inhibition of monoterpene cyclases by inert analogues of geranyl diphosphate and linalyl diphosphate
Arch. Biochem. Biophys.
468
140-146
2007
Salvia officinalis
Weitman, M.; Major, D.T.
Challenges posed to bornyl diphosphate synthase: diverging reaction mechanisms in monoterpenes
J. Am. Chem. Soc.
132
6349-6360
2010
Salvia officinalis (O81192)
Zhou, K.; Peters, R.J.
Electrostatic effects on (di)terpene synthase product outcome
Chem. Commun. (Camb. )
47
4074-4080
2011
Salvia officinalis
Schmiderer, C.; Grausgruber-Groeger, S.; Grassi, P.; Steinborn, R.; Novak, J.
Influence of gibberellin and daminozide on the expression of terpene synthases and on monoterpenes in common sage (Salvia officinalis)
J. Plant Physiol.
167
779-786
2010
Salvia officinalis (O81192)
O'Brien, T.; Bertolani, S.; Zhang, Y.; Siegel, J.; Tantillo, D.
Predicting productive binding modes for substrates and carbocation intermediates in terpene synthases - bornyl diphosphate synthase as a representative case
ACS Catal.
8
3322-3330
2018
Salvia officinalis (O81192)
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