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4.2.3.200

Accepted name:

β-pinacene synthase

Reaction:

geranylgeranyl diphosphate = β-pinacene + diphosphate

For diagram of cembrene and related diterpenoids, click here

Glossary:

β-pinacene = 4,8,12-trimethyl-1-(propan-2-yl)cyclotetradeca-1,3,7,11-tetraene

Other name(s):

PcS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, β-pinacene-forming)

Comments:

Isolated from the slime mould Dictyostelium discoideum. The 1-proR hydrogen atom of geranylgeranyl diphosphate is lost in the reaction.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Rinkel, J., Rabe, P., Chen, X., Kollner, T.G., Chen, F. and Dickschat, J.S. Mechanisms of the diterpene cyclases β-pinacene synthase from Dictyostelium discoideum and hydropyrene synthase from Streptomyces clavuligerus. Chem. Eur. J. 23 (2017) 10501–10505. [PMID: 28696553]

[EC 4.2.3.200 created 2018]

4.2.3.201

Accepted name:

hydropyrene synthase

Reaction:

geranylgeranyl diphosphate = hydropyrene + diphosphate

For mechanism, click here and for diagram of miscellaneous diterpenoid biosynthesis, click here

Glossary:

hydropyrene = (1R,3aR,3a¹R,5aR,5a¹S,8aS,10aS)-1,5a,8a-trimethyl-4-methylidenehexadecahydropyrene

Other name(s):

HpS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, hydropyrene-forming)

Comments:

Isolated from the bacterium Streptomyces clavuligerus. The 1-proR hydrogen atom of geranylgeranyl diphosphate is lost in the reaction. The enzyme also produces hydropyrenol, isoelisabethatriene and traces of other diterpenoids. cf. EC 4.2.3.202, hydropyrenol synthase, and EC 4.2.3.203, isoelisabethatriene synthase.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Rinkel, J., Rabe, P., Chen, X., Kollner, T.G., Chen, F. and Dickschat, J.S. Mechanisms of the diterpene cyclases β-pinacene synthase from Dictyostelium discoideum and hydropyrene synthase from Streptomyces clavuligerus. Chem. Eur. J. 23 (2017) 10501–10505. [PMID: 28696553]

[EC 4.2.3.201 created 2019]

4.2.3.202

Accepted name:

hydropyrenol synthase

Reaction:

geranylgeranyl diphosphate + H₂O = hydropyrenol + diphosphate

For mechanism, click here and for diagram of miscellaneous diterpenoid biosynthesis, click here

Glossary:

hydropyrenol = (1R,3aR,3a¹S,4S,5aR,5a¹S,8aS,10aS)-1,4,5a,8a-tetramethylhexadecahydropyren-4-ol

Other name(s):

HpS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, hydropyrenol-forming)

Comments:

Isolated from the bacterium Streptomyces clavuligerus. The 1-proR hydrogen atom of geranylgeranyl diphosphate is lost in the reaction. The enzyme also produces hydropyrene, isoelisabethatriene and traces of other diterpenoids. cf. EC 4.2.3.201, hydropyrene synthase, and EC 4.2.3.203, isoelisabethatriene synthase.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Rinkel, J., Rabe, P., Chen, X., Kollner, T.G., Chen, F. and Dickschat, J.S. Mechanisms of the diterpene cyclases β-pinacene synthase from Dictyostelium discoideum and hydropyrene synthase from Streptomyces clavuligerus. Chem. Eur. J. 23 (2017) 10501–10505. [PMID: 28696553]

[EC 4.2.3.202 created 2019]

4.2.3.203

Accepted name:

isoelisabethatriene synthase

Reaction:

geranylgeranyl diphosphate = isoelisabethatriene + diphosphate

For mechanism, click here and for diagram of miscellaneous diterpenoid biosynthesis, click here

Glossary:

isoelisabethatriene = (1S,4R)-4,7-dimethyl-1-[(2R)-6-methylhept-5-en-2-yl]-1,2,3,4,5,6-hexahydronaphthalene

Other name(s):

HpS (ambiguous)

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, isoelisabethatriene-forming)

Comments:

Isolated from the bacterium Streptomyces clavuligerus. The 1-proR hydrogen atom of geranylgeranyl diphosphate is involved in a 1,3-hydride shift to the side-chain. The enzyme also produces hydropyrene, hydropyrenol, and traces of other diterpenoids. cf. EC 4.2.3.201, hydropyrene synthase, and EC 4.2.3.202, hydropyrenol synthase.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Rinkel, J., Rabe, P., Chen, X., Kollner, T.G., Chen, F. and Dickschat, J.S. Mechanisms of the diterpene cyclases β-pinacene synthase from Dictyostelium discoideum and hydropyrene synthase from Streptomyces clavuligerus. Chem. Eur. J. 23 (2017) 10501–10505. [PMID: 28696553]

[EC 4.2.3.203 created 2019]

4.2.3.206

Accepted name:

(–)-cyatha-3,12-diene synthase

Reaction:

geranylgeranyl diphosphate = (–)-cyatha-3,12-diene + diphosphate

For diagram of related fungal and bacterial diterpenoids, click here

Glossary:

(–)-cyatha-3,12-diene = (3aS,5aS,10aS)-3a,5a,8-trimethyl-1-(propan-2-yl)-2,3,4,5,6,9,10,10a-octahydrocyclohepta[e]indene

Other name(s):

eriG (gene name); CyaTC

Systematic name:

geranylgeranyl diphosphate-lyase [(–)-cyatha-3,12-diene-forming]

Comments:

The enzyme, characterized from the fungi Hericium erinaceus and Cyathus africanus, requires Mg²⁺ for activity.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Yang, Y.L., Zhang, S., Ma, K., Xu, Y., Tao, Q., Chen, Y., Chen, J., Guo, S., Ren, J., Wang, W., Tao, Y., Yin, W.B. and Liu, H. Discovery and characterization of a new family of diterpene cyclases in bacteria and fungi. Angew. Chem. Int. Ed. Engl. 56 (2017) 4749–4752. [DOI] [PMID: 28371074]

[EC 4.2.3.206 created 2022]

4.2.3.207

Accepted name:

neoverrucosan-5β-ol synthase

Reaction:

geranylgeranyl diphosphate + H₂O = neoverrucosan-5β-ol + diphosphate

For diagram of related fungal and bacterial diterpenoids, click here

Glossary:

neoverrucosan-5β-ol = (1aS,3R,3aS,5aR,8S,8aR,8bR,8cS)-1a,3a,5a-trimethyl-8-(propan-2-yl)tetradecahydrocyclopenta[a]cyclopropa[h]naphthalen-3-ol

Other name(s):

SapTC1

Systematic name:

geranylgeranyl- diphosphate diphosphate-lyase (neoverrucosan-5β-ol-forming)

Comments:

Requires Mg²⁺. Characterized from the marine bacterium Saprospira grandis.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Yang, Y.L., Zhang, S., Ma, K., Xu, Y., Tao, Q., Chen, Y., Chen, J., Guo, S., Ren, J., Wang, W., Tao, Y., Yin, W.B. and Liu, H. Discovery and characterization of a new family of diterpene cyclases in bacteria and fungi. Angew. Chem. Int. Ed. Engl. 56 (2017) 4749–4752. [DOI] [PMID: 28371074]

[EC 4.2.3.207 created 2022]

4.2.3.208

Accepted name:

verrucosan-2β-ol synthase

Reaction:

geranylgeranyl diphosphate + H₂O = verrucosan-2β-ol + diphosphate

For diagram of related fungal and bacterial diterpenoids, click here

Glossary:

verrucosan-2β-ol = (1S,3aR,5aS,6aR,7aR,8S,8aR,9bR)-1-(propan=2-yl)tetradecahydrocyclopenta[a]cyclopropa[g]naphthalene-8-ol

Other name(s):

ChlTC2

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (verrucosan-2β-ol-forming)

Comments:

Requires Mg²⁺. Characterized from the bacterium Chloroflexus aurantiacus.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Yang, Y.L., Zhang, S., Ma, K., Xu, Y., Tao, Q., Chen, Y., Chen, J., Guo, S., Ren, J., Wang, W., Tao, Y., Yin, W.B. and Liu, H. Discovery and characterization of a new family of diterpene cyclases in bacteria and fungi. Angew. Chem. Int. Ed. Engl. 56 (2017) 4749–4752. [DOI] [PMID: 28371074]

[EC 4.2.3.208 created 2022]

4.2.3.209

Accepted name:

(R)-axinyssene synthase

Reaction:

geranylgeranyl diphosphate = (R)-axinyssene + diphosphate

For diagram of miscellaneous diterpenoid biosynthesis, click here

Glossary:

(R)-axinyssene = (4R)-4-[(5E)-6,10-dimethylundeca-1,5,9-trien-2-yl]-1-methylcyclohexene

Other name(s):

CysTC2

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase [(R)-axinyssene-forming]

Comments:

Requires Mg²⁺. Characterized from the bacterium Archangium violaceum.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Yang, Y.L., Zhang, S., Ma, K., Xu, Y., Tao, Q., Chen, Y., Chen, J., Guo, S., Ren, J., Wang, W., Tao, Y., Yin, W.B. and Liu, H. Discovery and characterization of a new family of diterpene cyclases in bacteria and fungi. Angew. Chem. Int. Ed. Engl. 56 (2017) 4749–4752. [DOI] [PMID: 28371074]

[EC 4.2.3.209 created 2022]

4.2.3.210

Accepted name:

lydicene synthase

Reaction:

geranylgeranyl diphosphate = lydicene + diphosphate

For diagram of related fungal and bacterial diterpenoids, click here

Glossary:

lydicene = (4aR,6aS)-2,2,4α,6α,9-pentamethyl-1,3,4,5,6,7,10,11-octahydro-1H-cyclohepta[a]naphthalene

Other name(s):

StlTC

Systematic name:

geranylgerany-diphosphate diphosphate-lyase (lydicene-forming)

Comments:

Requires Mg²⁺. Characterized from the bacterium Streptomyces lydicus.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Yang, Y.L., Zhang, S., Ma, K., Xu, Y., Tao, Q., Chen, Y., Chen, J., Guo, S., Ren, J., Wang, W., Tao, Y., Yin, W.B. and Liu, H. Discovery and characterization of a new family of diterpene cyclases in bacteria and fungi. Angew. Chem. Int. Ed. Engl. 56 (2017) 4749–4752. [DOI] [PMID: 28371074]

[EC 4.2.3.210 created 2022]

4.2.3.214

Accepted name:

dolasta-1(15),8-diene synthase

Reaction:

geranylgeranyl diphosphate = (5R,12R,14S)-dolasta-1(15),8-diene + diphosphate

For diagram of dolastadiene and δ-araneosene biosynthesis, click here

Glossary:

(5R,12R,14S)-dolasta-1(15),8-diene = (3aR,4aS,8aR)-3a,8a-dimethyl-5-methylene-1-(propan-2-yl)-2,3,3a,4,4a,5,6,7,8,8a,9,10-dodecahydrobenzo[f]azulene

Other name(s):

Cg113742 (gene name); CgDS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase [cyclizing, dolasta-1(15),8-diene-forming]

Comments:

Isolated from Colletotrichum gloeosporioides, a pathogenic fungus that causes bitter rot in variety of crops.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Bian, G., Rinkel, J., Wang, Z., Lauterbach, L., Hou, A., Yuan, Y., Deng, Z., Liu, T. and Dickschat, J.S. A clade II-D fungal chimeric diterpene synthase from Colletotrichum gloeosporioides produces dolasta-1(15),8-diene. Angew. Chem. Int. Ed. Engl. 57 (2018) 15887–15890. [DOI] [PMID: 30277637]

[EC 4.2.3.214 created 2023]

4.2.3.215

Accepted name:

δ-araneosene synthase

Reaction:

geranylgeranyl diphosphate = δ-araneosene + diphosphate

Glossary:

δ-araneosene = (3aR,5E,9E)-3a,6,10-trimethyl-1-(propan-2-yl)-2,3,3a,4,7,8,11,12-octahydrocyclopenta[11]annulene

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase [cyclizing, δ-araneosene-forming]

Comments:

Isolated from the fungus Colletotrichum gloeosporioidea. δ-Araneosene may be involved in the biosynthesis of dolasta-1(15),8-diene (see EC 4.2.3.214, dolasta-1(15),8-diene synthase) and cycloaraneosene (see EC 4.2.3.191, cycloaraneosene synthase).

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Bian, G., Rinkel, J., Wang, Z., Lauterbach, L., Hou, A., Yuan, Y., Deng, Z., Liu, T. and Dickschat, J.S. A clade II-D fungal chimeric diterpene synthase from Colletotrichum gloeosporioides produces dolasta-1(15),8-diene. Angew. Chem. Int. Ed. Engl. 57 (2018) 15887–15890. [DOI] [PMID: 30277637]

[EC 4.2.3.215 created 2023]

4.2.3.218

Accepted name:

variediene synthase

Reaction:

geranylgeranyl diphosphate = variediene + diphosphate

For diagram of miscellaneous diterpenoid biosynthesis, click here

Glossary:

variediene = (3aR,3bS,6E,10Z,11aR)-3,3,6,10,11a-pentamethyl-2,3,3a,3b,4,5,8,9,11,11a-decahydro-1H-cyclonona[a]pentalene

Other name(s):

EvVS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, variediene-forming)

Comments:

A diterpenoid synthase enzyme isolated from the fungus Aspergillus stellatus.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

Qin, B., Matsuda, Y., Mori, T., Okada, M., Quan, Z., Mitsuhashi, T., Wakimoto, T. and Abe, I. An unusual chimeric diterpene synthase from Emericella variecolor and its functional conversion into a sesterterpene synthase by domain swapping. Angew. Chem. Int. Ed. Engl. 55 (2016) 1658–1661. [DOI] [PMID: 26546087]

[EC 4.2.3.218 created 2023]

4.2.3.222

Accepted name:

phomopsene synthase

Reaction:

geranylgeranyl diphosphate = phomopsene + diphosphate

Glossary:

phomopsene = (1S,6aS,6bR,9aR,10aS)-1,4,7,7,9a-pentamethyl-1,2,3,5,6,6a,6b,7,8,9,9a,10-dodecahydrodicyclopenta[a,d]indene

Other name(s):

PaPS; NtPS; NrPS; PmS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, phomopsene-formimg)

Comments:

A diterpene synthase from the fungus Diaporthe amygdali. Phomopsene synthase has also been isolated from the bacteria Nocardia testacea, Nocardia rhamnosiphila, and Allokutzneria albata. The Allokutzneria albata enzyme also generates allokutznerene (EC 4.2.3.224, allokutznerene synthase), bonnadiene (EC 4.2.3.223, bonnadiene synthase) and traces of (–)-spiroviolene (EC 4.2.3.158, (–)-spiroviolene synthase).

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Toyomasu, T., Kaneko, A., Tokiwano, T., Kanno, Y., Kanno, Y., Niida, R., Miura, S., Nishioka, T., Ikeda, C., Mitsuhashi, W., Dairi, T., Kawano, T., Oikawa, H., Kato, N. and Sassa, T. Biosynthetic gene-based secondary metabolite screening: a new diterpene, methyl phomopsenonate, from the fungus Phomopsis amygdali. J. Org. Chem. 74 (2009) 1541–1548. [DOI] [PMID: 19161275]
2.	Shinde, S.S., Minami, A., Chen, Z., Tokiwano, T., Toyomasu, T., Kato, N., Sassa, T. and Oikawa, H. Cyclization mechanism of phomopsene synthase: mass spectrometry based analysis of various site-specifically labeled terpenes. J. Antibiot. (Tokyo) 70 (2017) 632–638. [DOI] [PMID: 28270685]
3.	Lauterbach, L., Rinkel, J. and Dickschat, J.S. Two bacterial diterpene synthases from Allokutzneria albata produce bonnadiene, phomopsene, and allokutznerene. Angew. Chem. Int. Ed. Engl. 57 (2018) 8280–8283. [DOI] [PMID: 29758116]
4.	Rinkel, J., Steiner, S.T. and Dickschat, J.S. Diterpene biosynthesis in actinomycetes: studies on cattleyene synthase and phomopsene synthase. Angew. Chem. Int. Ed. Engl. 58 (2019) 9230–9233. [DOI] [PMID: 31034729]

[EC 4.2.3.222 created 2024]

4.2.3.223

Accepted name:

bonnadiene synthase

Reaction:

geranylgeranyl diphosphate = bonnadiene + diphosphate

Glossary:

bonnadiene = (1R,7R,7aR,11aR)-1,4,9-trimethyl-7-(propan-2-yl)-2,3,5,6,7,7a,10,11-octahydro-1H-benzo[d]azulene

Other name(s):

BdS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, bonnadiene-formimg)

Comments:

A diterpene synthase isolated from the bacterium Allokutzneria albata. It also generates allokutznerene (EC 4.2.3.224, allokutznerene synthase), phomopsene (EC 4.2.3.222, phomopsene synthase) and traces of (–)-spiroviolene (EC 4.2.3.158, (–)-spiroviolene synthase).

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Lauterbach, L., Rinkel, J. and Dickschat, J.S. Two bacterial diterpene synthases from Allokutzneria albata produce bonnadiene, phomopsene, and allokutznerene. Angew. Chem. Int. Ed. Engl. 57 (2018) 8280–8283. [DOI] [PMID: 29758116]

[EC 4.2.3.223 created 2024]

4.2.3.224

Accepted name:

allokutznerene synthase

Reaction:

geranylgeranyl diphosphate = allokutznerene + diphosphate

Glossary:

allokutznerene = (3S,3aS,7aR,10aR,10bS)-3,6,7a,10,10-pentamethyl-1,2,3,4,5,7,7a,8,9,10,10a,10b-dodecahydrodicyclopenta[d,g]indene

Other name(s):

PmS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, allokutznerene-formimg)

Comments:

A diterpene synthase isolated from the bacterium Allokutzneria albata. It also produces bonnadiene (EC 4.2.3.223, bonnadiene synthase), phomopsene (EC 4.2.3.222, phomopsene synthase) and traces of (–)-spiroviolene (EC 4.2.3.158, (–)-spiroviolene synthase).

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Lauterbach, L., Rinkel, J. and Dickschat, J.S. Two bacterial diterpene synthases from Allokutzneria albata produce bonnadiene, phomopsene, and allokutznerene. Angew. Chem. Int. Ed. Engl. 57 (2018) 8280–8283. [DOI] [PMID: 29758116]

[EC 4.2.3.224 created 2024]

4.2.3.225

Accepted name:

cattleyene synthase

Reaction:

geranylgeranyl diphosphate = cattleyene + diphosphate

Glossary:

cattleyene = (3R,3aS,5aS,5bR,8aR)-3,3a,6,6,8a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,8,8a,9-dodecahydro-1H-pentaleno[2,1-e]indene

Other name(s):

CyS

Systematic name:

geranylgeranyl-diphosphate diphosphate-lyase (cyclizing, cattleyene-formimg)

Comments:

A diterpene synthase isolated from the bacterium Streptantibioticus cattleyicolor.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Rinkel, J., Steiner, S.T. and Dickschat, J.S. Diterpene biosynthesis in actinomycetes: studies on cattleyene synthase and phomopsene synthase. Angew. Chem. Int. Ed. Engl. 58 (2019) 9230–9233. [DOI] [PMID: 31034729]
2.	Xing, B., Xu, H., Li, A., Lou, T., Xu, M., Wang, K., Xu, Z., Dickschat, J.S., Yang, D. and Ma, M. Crystal structure based mutagenesis of cattleyene synthase leads to the generation of rearranged polycyclic diterpenes. Angew. Chem. Int. Ed. Engl. 61:e202209785 (2022). [DOI] [PMID: 35819825]

[EC 4.2.3.225 created 2024]

4.2.3.228

Accepted name:

(Z)-β-ocimene synthase

Reaction:

geranyl diphosphate = (Z)-β-ocimene + diphosphate

For diagram of acyclic monoterpenoid biosynthesis, click here

Glossary:

(Z)-β-ocimene = (3Z)-3,7-dimethyl-1,3,6-octatriene

Other name(s):

CsTPS13PK (gene name)

Systematic name:

geranyl diphosphate diphosphate lyase [(Z)-β-ocimene-forming]

Comments:

The enzyme occurs in flowers (pistillate inflorescences) of Cannabis sativa. The enzyme encoded by CsTPS13PK produces 94% (Z)-β-ocimene from geranyl diphosphate. cf. EC 4.2.3.106, (E)-β-ocimene synthase.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Booth, J.K., Page, J.E. and Bohlmann, J. Terpene synthases from Cannabis sativa. PLoS One 12:e0173911 (2017). [DOI] [PMID: 28355238]

[EC 4.2.3.228 created 2024]

5.5.1.8

Accepted name:

(+)-bornyl diphosphate synthase

Reaction:

geranyl diphosphate = (+)-bornyl diphosphate

For diagram of bornane and related monoterpenoids, click here

Glossary:

(+)-bornyl diphosphate = (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl diphosphate

Other name(s):

bornyl pyrophosphate synthase (ambiguous); bornyl pyrophosphate synthetase (ambiguous); (+)-bornylpyrophosphate cyclase; geranyl-diphosphate cyclase (ambiguous); (+)-bornyl-diphosphate lyase (decyclizing)

Systematic name:

(+)-bornyl-diphosphate lyase (ring-opening)

Comments:

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].

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 72668-91-8

References:

1.	Croteau, R. and 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 (1979) 512–522. [DOI] [PMID: 42356]
2.	Croteau, R., Gershenzon, J., Wheeler, C.J. and Satterwhite, D.M. Biosynthesis of monoterpenes: stereochemistry of the coupled isomerization and cyclization of geranyl pyrophosphate to camphane and isocamphane monoterpenes. Arch. Biochem. Biophys. 277 (1990) 374–381. [DOI] [PMID: 2178556]
3.	Croteau, R., Satterwhite, D.M., Cane, D.E. and Chang, C.C. Biosynthesis of monoterpenes. Enantioselectivity in the enzymatic cyclization of (+)- and (-)-linalyl pyrophosphate to (+)- and (-)-bornyl pyrophosphate. J. Biol. Chem. 261 (1986) 13438–13445. [PMID: 3759972]
4.	Croteau, R., Felton, N.M. and Wheeler, C.J. Stereochemistry at C-1 of geranyl pyrophosphate and neryl pyrophosphate in the cyclization to (+)- and (-)-bornyl pyrophosphate. J. Biol. Chem. 260 (1985) 5956–5962. [PMID: 3997807]
5.	Croteau, R.B., Shaskus, J.J., Renstrom, B., Felton, N.M., Cane, D.E., Saito, A. and Chang, C. Mechanism of the pyrophosphate migration in the enzymatic cyclization of geranyl and linalyl pyrophosphates to (+)- and (-)-bornyl pyrophosphates. Biochemistry 24 (1985) 7077–7085. [PMID: 4084562]
6.	McGeady, P. and Croteau, R. Isolation and characterization of an active-site peptide from a monoterpene cyclase labeled with a mechanism-based inhibitor. Arch. Biochem. Biophys. 317 (1995) 149–155. [DOI] [PMID: 7872777]
7.	Wise, M.L., Savage, T.J., Katahira, E. and 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 (1998) 14891–14899. [DOI] [PMID: 9614092]
8.	Whittington, D.A., Wise, M.L., Urbansky, M., Coates, R.M., Croteau, R.B. and Christianson, D.W. Bornyl diphosphate synthase: structure and strategy for carbocation manipulation by a terpenoid cyclase. Proc. Natl. Acad. Sci. USA 99 (2002) 15375–15380. [DOI] [PMID: 12432096]
9.	Peters, R.J. and Croteau, R.B. Alternative termination chemistries utilized by monoterpene cyclases: chimeric analysis of bornyl diphosphate, 1,8-cineole, and sabinene synthases. Arch. Biochem. Biophys. 417 (2003) 203–211. [DOI] [PMID: 12941302]

[EC 5.5.1.8 created 1984, modified 2012]

5.5.1.12

Accepted name:

copalyl diphosphate synthase

Reaction:

geranylgeranyl diphosphate = (+)-copalyl diphosphate

For diagram of abietadiene, abietate, isopimaradiene, labdadienol and sclareol biosynthesis, click here, for diagram of labdane diterpenoids biosynthesis, click here and for diagram of pimarane diterpenoids biosynthesis, click here

Other name(s):

(+)-copalyl-diphosphate lyase (decyclizing)

Systematic name:

(+)-copalyl-diphosphate lyase (ring-opening)

Comments:

In some plants, such as Salvia miltiorrhiza, this enzyme is monofunctional. In other plants this activity is often a part of a bifunctional enzyme. For example, in Selaginella moellendorffii this activity is catalysed by a bifunctional enzyme that also catalyses EC 4.2.3.131, miltiradiene synthase, while in the tree Abies grandis (grand fir) it is catalysed by a bifunctional enzyme that also catalyses EC 4.2.3.18, abietadiene synthase.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 157972-08-2

References:

1.	Peters, R.J., Ravn, M.M., Coates, R.M. and Croteau, R.B. Bifunctional abietadiene synthase: free diffusive transfer of the (+)-copalyl diphosphate intermediate between two distinct active sites. J. Am. Chem. Soc. 123 (2001) 8974–8978. [DOI] [PMID: 11552804]
2.	Sugai, Y., Ueno, Y., Hayashi, K., Oogami, S., Toyomasu, T., Matsumoto, S., Natsume, M., Nozaki, H. and Kawaide, H. Enzymatic ¹³C labeling and multidimensional NMR analysis of miltiradiene synthesized by bifunctional diterpene cyclase in Selaginella moellendorffii. J. Biol. Chem. 286 (2011) 42840–42847. [DOI] [PMID: 22027823]
3.	Peters, R.J. and Croteau, R.B. Abietadiene synthase catalysis: mutational analysis of a prenyl diphosphate ionization-initiated cyclization and rearrangement. Proc. Natl. Acad. Sci. USA 99 (2002) 580–584. [DOI] [PMID: 11805316]
4.	Ravn, M.M., Peters, R.J., Coates, R.M. and Croteau, R. Mechanism of abietadiene synthase catalysis: stereochemistry and stabilization of the cryptic pimarenyl carbocation intermediates. J. Am. Chem. Soc. 124 (2002) 6998–7006. [DOI] [PMID: 12059223]
5.	Peters, R.J. and Croteau, R.B. Abietadiene synthase catalysis: conserved residues involved in protonation-initiated cyclization of geranylgeranyl diphosphate to (+)-copalyl diphosphate. Biochemistry 41 (2002) 1836–1842. [DOI] [PMID: 11827528]

[EC 5.5.1.12 created 2002, modified 2012]

5.5.1.13

Accepted name:

ent-copalyl diphosphate synthase

Reaction:

geranylgeranyl diphosphate = ent-copalyl diphosphate

For diagram of biosynthesis of diterpenoids from ent-copalyl diphosphate, click here

Other name(s):

ent-kaurene synthase A; ent-kaurene synthetase A; ent-CDP synthase; ent-copalyl-diphosphate lyase (decyclizing)

Systematic name:

ent-copalyl-diphosphate lyase (ring-opening)

Comments:

Part of a bifunctional enzyme involved in the biosynthesis of kaurene. See also EC 4.2.3.19 (ent-kaurene synthase)

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9055-64-5

References:

1.	Fall, R.R., West, C.A. Purification and properties of kaurene synthetase from Fusarium moniliforme. J. Biol. Chem. 246 (1971) 6913–6928. [PMID: 4331199]
2.	Sun, T.P. and Kamiya, Y. The Arabidopsis GA1 locus encodes the cyclase ent-kaurene synthetase A of gibberellin biosynthesis. Plant Cell 6 (1994) 1509–1518. [PMID: 7994182]
3.	Kawaide, H., Imai, R., Sassa, T. and Kamiya, Y. Ent-kaurene synthase from the fungus Phaeosphaeria sp. L487. cDNA isolation, characterization, and bacterial expression of a bifunctional diterpene cyclase in fungal gibberellin biosynthesis. J. Biol. Chem. 272 (1997) 21706–21712. [DOI] [PMID: 9268298]
4.	Toyomasu, T., Kawaide, H., Ishizaki, A., Shinoda, S., Otsuka, M., Mitsuhashi, W. and Sassa, T. Cloning of a full-length cDNA encoding ent-kaurene synthase from Gibberella fujikuroi: functional analysis of a bifunctional diterpene cyclase. Biosci. Biotechnol. Biochem. 64 (2000) 660–664. [DOI] [PMID: 10803977]

[EC 5.5.1.13 created 2002]

5.5.1.14

Accepted name:

syn-copalyl-diphosphate synthase

Reaction:

geranylgeranyl diphosphate = 9α-copalyl diphosphate

For diagram of diterpenoids from 9α-copalyl diphosphate, click here

Glossary:

syn-copalyl diphosphate = 9α-copalyl diphosphate

Other name(s):

OsCyc1; OsCPSsyn; syn-CPP synthase; syn-copalyl diphosphate synthase; 9α-copalyl-diphosphate lyase (decyclizing)

Systematic name:

9α-copalyl-diphosphate lyase (ring-opening)

Comments:

Requires a divalent metal ion, preferably Mg²⁺, for activity. This class II terpene synthase produces syn-copalyl diphosphate, a precursor of several rice phytoalexins, including oryzalexin S and momilactones A and B. Phytoalexins are diterpenoid secondary metabolites that are involved in the defense mechanism of the plant, and are produced in response to pathogen attack through the perception of elicitor signal molecules such as chitin oligosaccharide, or after exposure to UV irradiation. The enzyme is constitutively expressed in the roots of plants where one of its products, momilactone B, acts as an allelochemical (a molecule released into the environment to suppress the growth of neighbouring plants). In other tissues the enzyme is upregulated by conditions that stimulate the biosynthesis of phytoalexins.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, PDB

References:

1.	Otomo, K., Kenmoku, H., Oikawa, H., Konig, W.A., Toshima, H., Mitsuhashi, W., Yamane, H., Sassa, T. and Toyomasu, T. Biological functions of ent- and syn-copalyl diphosphate synthases in rice: key enzymes for the branch point of gibberellin and phytoalexin biosynthesis. Plant J. 39 (2004) 886–893. [DOI] [PMID: 15341631]
2.	Xu, M., Hillwig, M.L., Prisic, S., Coates, R.M. and Peters, R.J. Functional identification of rice syn-copalyl diphosphate synthase and its role in initiating biosynthesis of diterpenoid phytoalexin/allelopathic natural products. Plant J. 39 (2004) 309–318. [DOI] [PMID: 15255861]

[EC 5.5.1.14 created 2008]

5.5.1.15

Accepted name:

terpentedienyl-diphosphate synthase

Reaction:

geranylgeranyl diphosphate = terpentedienyl diphosphate

For diagram of diterpenoid biosynthesis, click here

Glossary:

terpentedienyl diphosphate = (2E)-3-methyl-5-[(1R,2R,4aS,8aS)-1,2,4a,5-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl]pent-2-en-1-yl diphosphate

Other name(s):

terpentedienol diphosphate synthase; Cyc1; clerodadienyl diphosphate synthase; terpentedienyl-diphosphate lyase (decyclizing)

Systematic name:

terpentedienyl-diphosphate lyase (ring-opening)

Comments:

Requires Mg²⁺. Contains a DXDD motif, which is a characteristic of diterpene cylases whose reactions are initiated by protonation at the 14,15-double bond of geranylgeranyl diphosphate (GGDP) [2]. The triggering proton is lost at the end of the cyclization reaction [3]. The product of the reaction, terpentedienyl diphosphate, is the substrate for EC 4.2.3.36, terpentetriene synthase and is a precursor of the diterpenoid antibiotic terpentecin.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Dairi, T., Hamano, Y., Kuzuyama, T., Itoh, N., Furihata, K. and Seto, H. Eubacterial diterpene cyclase genes essential for production of the isoprenoid antibiotic terpentecin. J. Bacteriol. 183 (2001) 6085–6094. [DOI] [PMID: 11567009]
2.	Hamano, Y., Kuzuyama, T., Itoh, N., Furihata, K., Seto, H. and Dairi, T. Functional analysis of eubacterial diterpene cyclases responsible for biosynthesis of a diterpene antibiotic, terpentecin. J. Biol. Chem. 277 (2002) 37098–37104. [DOI] [PMID: 12138123]
3.	Eguchi, T., Dekishima, Y., Hamano, Y., Dairi, T., Seto, H. and Kakinuma, K. A new approach for the investigation of isoprenoid biosynthesis featuring pathway switching, deuterium hyperlabeling, and ¹H NMR spectroscopy. The reaction mechanism of a novel streptomyces diterpene cyclase. J. Org. Chem. 68 (2003) 5433–5438. [DOI] [PMID: 12839434]

[EC 5.5.1.15 created 2008]

5.5.1.16

Accepted name:

halimadienyl-diphosphate synthase

Reaction:

geranylgeranyl diphosphate = tuberculosinyl diphosphate

For diagram of diterpenoid biosynthesis, click here

Glossary:

tuberculosinyl diphosphate = halima-5,13-dien-15-yl diphosphate

Other name(s):

Rv3377c; halimadienyl diphosphate synthase; tuberculosinol diphosphate synthase; halima-5(6),13-dien-15-yl-diphosphate lyase (cyclizing); halima-5,13-dien-15-yl-diphosphate lyase (decyclizing)

Systematic name:

halima-5,13-dien-15-yl-diphosphate lyase (ring-opening)

Comments:

Requires Mg²⁺ for activity. This enzyme is found in pathogenic prokaryotes such as Mycobacterium tuberculosis but not in non-pathogens such as Mycobacterium smegmatis so may play a role in pathogenicity. The product of the reaction is subsequently dephosphorylated yielding tuberculosinol (halima-5,13-dien-15-ol).

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, PDB

References:

1.	Nakano, C., Okamura, T., Sato, T., Dairi, T. and Hoshino, T. Mycobacterium tuberculosis H37Rv3377c encodes the diterpene cyclase for producing the halimane skeleton. Chem. Commun. (Camb.) (2005) 1016–1018. [DOI] [PMID: 15719101]

[EC 5.5.1.16 created 2008, modified 2012]

5.5.1.22

Accepted name:

(–)-bornyl diphosphate synthase

Reaction:

geranyl diphosphate = (–)-bornyl diphosphate

For diagram of bornane and related monoterpenoids, click here

Glossary:

(–)-bornyl diphosphate = (2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl diphosphate

Other name(s):

bornyl pyrophosphate synthase (ambiguous); bornyl pyrophosphate synthetase (ambiguous); (–)-bornyl pyrophosphate cyclase; bornyl diphosphate synthase; geranyl-diphosphate cyclase (ambiguous); (–)-bornyl-diphosphate lyase (decyclizing)

Systematic name:

(–)-bornyl-diphosphate lyase (ring-opening)

Comments:

Requires Mg²⁺. The enzyme from Tanacetum vulgare (tansy) can also use (3S)-linalyl diphosphate or more slowly neryl diphosphate in vitro. The reaction proceeds via isomeration of geranyl diphosphate to (3S)-linalyl diphosphate [3]. The oxygen and phosphorus originally linked to C-1 of geranyl diphosphate end up linked to C-2 of (–)-bornyl diphosphate [4]. cf. EC 5.5.1.8 (+)-bornyl diphosphate synthase.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 110639-17-3

References:

1.	Croteau, R., Gershenzon, J., Wheeler, C.J. and Satterwhite, D.M. Biosynthesis of monoterpenes: stereochemistry of the coupled isomerization and cyclization of geranyl pyrophosphate to camphane and isocamphane monoterpenes. Arch. Biochem. Biophys. 277 (1990) 374–381. [DOI] [PMID: 2178556]
2.	Croteau, R. and Shaskus, J. Biosynthesis of monoterpenes: demonstration of a geranyl pyrophosphate:(-)-bornyl pyrophosphate cyclase in soluble enzyme preparations from tansy (Tanacetum vulgare). Arch. Biochem. Biophys. 236 (1985) 535–543. [DOI] [PMID: 3970524]
3.	Croteau, R., Felton, N.M. and Wheeler, C.J. Stereochemistry at C-1 of geranyl pyrophosphate and neryl pyrophosphate in the cyclization to (+)- and (-)-bornyl pyrophosphate. J. Biol. Chem. 260 (1985) 5956–5962. [PMID: 3997807]
4.	Croteau, R.B., Shaskus, J.J., Renstrom, B., Felton, N.M., Cane, D.E., Saito, A. and Chang, C. Mechanism of the pyrophosphate migration in the enzymatic cyclization of geranyl and linalyl pyrophosphates to (+)- and (-)-bornyl pyrophosphates. Biochemistry 24 (1985) 7077–7085. [PMID: 4084562]
5.	Adam, K.P. and Croteau, R. Monoterpene biosynthesis in the liverwort Conocephalum conicum: demonstration of sabinene synthase and bornyl diphosphate synthase. Phytochemistry 49 (1998) 475–480. [DOI] [PMID: 9747540]

[EC 5.5.1.22 created 2012]

5.5.1.28

Accepted name:

(–)-kolavenyl diphosphate synthase

Reaction:

geranylgeranyl diphosphate = (–)-kolavenyl diphosphate

For diagram of (–)-kolavenyl diphosphate derived diterpenoids, click here

Glossary:

(–)-kolavenyl diphosphate = (2E)-5-[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl]-3-methylpent-2-en-1-yl diposphate

Other name(s):

SdKPS; TwTPS14; TwTPS10/KPS; SdCPS2; clerodienyl diphosphate synthase; CLPP

Systematic name:

(–)-kolavenyl diphosphate lyase (ring-opening)

Comments:

Isolated from the hallucinogenic plant Salvia divinorum (seer’s sage) and the medicinal plant Tripterygium wilfordii (thunder god vine).

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Hansen, N.L., Heskes, A.M., Hamberger, B., Olsen, C.E., Hallstrom, B.M., Andersen-Ranberg, J. and Hamberger, B. The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily. Plant J. 89 (2017) 429–441. [DOI] [PMID: 27801964]
2.	Chen, X., Berim, A., Dayan, F.E. and Gang, D.R. A (–)-kolavenyl diphosphate synthase catalyzes the first step of salvinorin A biosynthesis in Salvia divinorum. J. Exp. Bot. 68 (2017) 1109–1122. [DOI] [PMID: 28204567]

[EC 5.5.1.28 created 2017]

5.5.1.29

Accepted name:

(+)-kolavenyl diphosphate synthase

Reaction:

geranylgeranyl diphosphate = (+)-kolavenyl diphosphate

For diagram of (+)-kolavenyl diphosphate derived diterpenoids, click here

Glossary:

(+) kolavenyl diphosphate = (2E)-3-methyl-5-[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl]pent-2-en-1-yl diphosphate

Systematic name:

(+)-kolavenyl-diphosphate lyase (ring-opening)

Comments:

Isolated from the bacterium Herpetosiphon aurantiacus.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Nakano, C., Oshima, M., Kurashima, N. and Hoshino, T. Identification of a new diterpene biosynthetic gene cluster that produces O-methylkolavelool in Herpetosiphon aurantiacus. ChemBioChem 16 (2015) 772–781. [DOI] [PMID: 25694050]

[EC 5.5.1.29 created 2017]

5.5.1.30

Accepted name:

labda-7,13-dienyl diphosphate synthase

Reaction:

geranylgeranyl diphosphate = (13E)-labda-7,13-dien-15-yl diphosphate

For diagram of labdane diterpenoids biosynthesis, click here

Other name(s):

SCLAV_p0490

Systematic name:

(13E)-labda-7,13-dien-15-yl-diphosphate lyase (ring-opening)

Comments:

Isolated from the bacterium Streptomyces clavuligerus.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc

References:

1.	Yamada, Y., Komatsu, M. and Ikeda, H. Chemical diversity of labdane-type bicyclic diterpene biosynthesis in Actinomycetales microorganisms. J. Antibiot. (Tokyo) 69 (2016) 515–523. [DOI] [PMID: 26814669]

[EC 5.5.1.30 created 2017]