EC 4.2.3.18     
Accepted name: abieta-7,13-diene synthase
Reaction: (+)-copalyl diphosphate = abieta-7,13-diene + diphosphate
Glossary: (+)-copalyl diphosphate = (2E)-3-methyl-5-[(1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl]pent-2-en-1-yl trihydrogen diphosphate
abieta-7,13-diene = (4aS,4bR,10aS)-7-isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene
Other name(s): copalyl-diphosphate diphosphate-lyase (cyclizing) (ambiguous); abietadiene synthase (ambiguous)
Systematic name: (+)-copalyl-diphosphate diphosphate-lyase [cyclizing, abieta-7,13-diene-forming]
Comments: Part of a bifunctional enzyme involved in the biosynthesis of abietadiene. See also EC 5.5.1.12, copalyl diphosphate synthase. Requires Mg2+.
References:
1.  Peters, R.J., Flory, J.E., Jetter, R., Ravn, M.M., Lee, H.J., Coates, R.M. and Croteau, R.B. Abietadiene synthase from grand fir (Abies grandis): characterization and mechanism of action of the "pseudomature" recombinant enzyme. Biochemistry 39 (2000) 15592–15602. [PMID: 11112547]
2.  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. [PMID: 11552804]
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. [PMID: 11805316]
4.  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. [PMID: 11827528]
5.  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. [PMID: 12059223]
[EC 4.2.3.18 created 2002, modified 2012]
 
 
EC 4.2.3.32     
Accepted name: levopimaradiene synthase
Reaction: (+)-copalyl diphosphate = abieta-8(14),12-diene + diphosphate
Glossary: levopimaradiene = abieta-8(14),12-diene
Other name(s): PtTPS-LAS; LPS; copalyl-diphosphate diphosphate-lyase [abieta-8(14),12-diene-forming]
Systematic name: (+)-copalyl-diphosphate diphosphate-lyase [abieta-8(14),12-diene-forming]
Comments: In Ginkgo, the enzyme catalyses the initial cyclization step in the biosynthesis of ginkgolides, a structurally unique family of diterpenoids that are highly specific platelet-activating-factor receptor antagonists [1]. Levopimaradiene is widely distributed in higher plants. In some species the enzyme also forms abietadiene, palustradiene, and neoabietadiene [2].
References:
1.  Schepmann, H.G., Pang, J. and Matsuda, S.P. Cloning and characterization of Ginkgo biloba levopimaradiene synthase which catalyzes the first committed step in ginkgolide biosynthesis. Arch. Biochem. Biophys. 392 (2001) 263–269. [PMID: 11488601]
2.  Ro, D.K. and Bohlmann, J. Diterpene resin acid biosynthesis in loblolly pine (Pinus taeda): functional characterization of abietadiene/levopimaradiene synthase (PtTPS-LAS) cDNA and subcellular targeting of PtTPS-LAS and abietadienol/abietadienal oxidase (PtAO, CYP720B1). Phytochemistry 67 (2006) 1572–1578. [PMID: 16497345]
[EC 4.2.3.32 created 2008, modified 2012]
 
 
EC 4.2.3.44     
Accepted name: isopimara-7,15-diene synthase
Reaction: (+)-copalyl diphosphate = isopimara-7,15-diene + diphosphate
Glossary: isopimara-7,15-diene = 13α-pimara-7,15-diene
Other name(s): PaTPS-Iso; copalyl diphosphate-lyase (isopimara-7,15-diene-forming)
Systematic name: (+)-copalyl diphosphate-lyase (isopimara-7,15-diene-forming)
Comments: The enzyme only gave isopimara-7,15-diene.
References:
1.  Martin, D.M., Faldt, J. and Bohlmann, J. Functional characterization of nine Norway Spruce TPS genes and evolution of gymnosperm terpene synthases of the TPS-d subfamily. Plant Physiol. 135 (2004) 1908–1927. [PMID: 15310829]
[EC 4.2.3.44 created 2009]
 
 
EC 4.2.3.45     
Accepted name: phyllocladan-16α-ol synthase
Reaction: (+)-copalyl diphosphate + H2O = phyllocladan-16α-ol + diphosphate
Other name(s): PaDC1
Systematic name: (+)-copalyl-diphosphate diphosphate-lyase (phyllocladan-16α-ol-forming)
Comments: The adjacent gene PaDC2 codes EC 5.5.1.12 copalyl diphosphate synthase.
References:
1.  Toyomasu, T., Niida, R., Kenmoku, H., Kanno, Y., Miura, S., Nakano, C., Shiono, Y., Mitsuhashi, W., Toshima, H., Oikawa, H., Hoshino, T., Dairi, T., Kato, N. and Sassa, T. Identification of diterpene biosynthetic gene clusters and functional analysis of labdane-related diterpene cyclases in Phomopsis amygdali. Biosci. Biotechnol. Biochem. 72 (2008) 1038–1047. [PMID: 18391465]
[EC 4.2.3.45 created 2009]
 
 
EC 4.2.3.131     
Accepted name: miltiradiene synthase
Reaction: (+)-copalyl diphosphate = miltiradiene + diphosphate
Other name(s): SmMDS; SmiKSL; RoKSL
Systematic name: (+)-copalyl-diphosphate diphosphate-lyase (cyclizing, miltiradiene-forming)
Comments: Isolated from the plants Rosmarinus officinalis (rosemary) and Salvia miltiorrhiza. The enzyme from the plant Selaginella moellendorffii is mutifunctional and also catalyses EC 5.5.1.12, copalyl diphosphate synthase [2].
References:
1.  Gao, W., Hillwig, M.L., Huang, L., Cui, G., Wang, X., Kong, J., Yang, B. and Peters, R.J. A functional genomics approach to tanshinone biosynthesis provides stereochemical insights. Org. Lett. 11 (2009) 5170–5173. [PMID: 19905026]
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. [PMID: 22027823]
3.  Bruckner, K., Bozic, D., Manzano, D., Papaefthimiou, D., Pateraki, I., Scheler, U., Ferrer, A., de Vos, R.C., Kanellis, A.K. and Tissier, A. Characterization of two genes for the biosynthesis of abietane-type diterpenes in rosemary (Rosmarinus officinalis) glandular trichomes. Phytochemistry 101 (2014) 52–64. [PMID: 24569175]
[EC 4.2.3.131 created 2012]
 
 
EC 4.2.3.132     
Accepted name: neoabietadiene synthase
Reaction: (+)-copalyl diphosphate = neoabietadiene + diphosphate
Glossary: neoabietadiene = abieta-8(14),13(15)-diene
Other name(s): TPS-LAS
Systematic name: (+)-copaly-diphosphate diphosphate-lyase (cyclizing, neoabietadiene-forming)
Comments: Isolated from Abies grandis (grand fir) [1]. This class I enzyme forms about equal proportions of abietadiene, levopimaradiene and neoabietadiene. See also EC 4.2.3.18, abieta-7,13-diene synthase and EC 4.2.3.32, levopimaradiene synthase. An X-ray study of this multifunctional enzyme showed that the class I activity is in the α domain, while (+)-copalyl diphosphate synthase activity (EC 5.5.1.12, a class II activity) is in the β and γ domains [2]. In Pinus taeda (loblolly pine) the major product is levopimaradiene, with less abietadiene and neoabietadiene [3].
References:
1.  Peters, R.J., Flory, J.E., Jetter, R., Ravn, M.M., Lee, H.J., Coates, R.M. and Croteau, R.B. Abietadiene synthase from grand fir (Abies grandis): characterization and mechanism of action of the "pseudomature" recombinant enzyme. Biochemistry 39 (2000) 15592–15602. [PMID: 11112547]
2.  Zhou, K., Gao, Y., Hoy, J.A., Mann, F.M., Honzatko, R.B. and Peters, R.J. Insights into diterpene cyclization from structure of bifunctional abietadiene synthase from Abies grandis. J. Biol. Chem. 287 (2012) 6840–6850. [PMID: 22219188]
3.  Ro, D.K. and Bohlmann, J. Diterpene resin acid biosynthesis in loblolly pine (Pinus taeda): functional characterization of abietadiene/levopimaradiene synthase (PtTPS-LAS) cDNA and subcellular targeting of PtTPS-LAS and abietadienol/abietadienal oxidase (PtAO, CYP720B1). Phytochemistry 67 (2006) 1572–1578. [PMID: 16497345]
[EC 4.2.3.132 created 2012]
 
 
EC 4.2.3.147     
Accepted name: pimaradiene synthase
Reaction: (+)-copalyl diphosphate = pimara-8(14),15-diene + diphosphate
Other name(s): PbmPIM1; PcmPIM1
Systematic name: (+)-copalyl diphosphate-lyase (pimara-8(14),15-diene-forming)
Comments: Isolated from the plants Pinus banksiana (jack pine) and Pinus contorta (lodgepole pine).
References:
1.  Hall, D.E., Zerbe, P., Jancsik, S., Quesada, A.L., Dullat, H., Madilao, L.L., Yuen, M. and Bohlmann, J. Evolution of conifer diterpene synthases: diterpene resin acid biosynthesis in lodgepole pine and jack pine involves monofunctional and bifunctional diterpene synthases. Plant Physiol. 161 (2013) 600–616. [PMID: 23370714]
[EC 4.2.3.147 created 2014]
 
 
EC 4.2.3.183     
Accepted name: nezukol synthase
Reaction: (+)-copalyl diphosphate + H2O = nezukol + diphosphate
Glossary: (+)-copalyl diphosphate = (2E)-3-methyl-5-[(1S,4aS,8aS)-5,5,8a-trimethyl-2-methylidenedecahydronaphthalen-1-yl]pent-2-en-1-yl trihydrogen diphosphate
nezukol = pimar-15-en-8-ol
Other name(s): TPS2
Systematic name: (+)-copalyl-diphosphate diphosphate-lyase (cyclizing, nezukol-forming)
Comments: Isolated from the plant Isodon rubescens.
References:
1.  Pelot, K.A., Hagelthorn, D.M., Addison, J.B. and Zerbe, P. Biosynthesis of the oxygenated diterpene nezukol in the medicinal plant Isodon rubescens is catalyzed by a pair of diterpene synthases. PLoS One 12:e0176507 (2017). [PMID: 28445526]
[EC 4.2.3.183 created 2017]
 
 
EC 4.2.3.193     
Accepted name: (12E)-labda-8(17),12,14-triene synthase
Reaction: (+)-copalyl diphosphate = (12E)-labda-8(17),12,14-triene + diphosphate
Other name(s): CldD
Systematic name: (+)-copalyl-diphosphate diphosphate-lyase [(12E)-labda-8(17),12,14-triene-forming]
Comments: Isolated from the bacterium Streptomyces cyslabdanicus.
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. [PMID: 26814669]
[EC 4.2.3.193 created 2017]
 
 
EC 5.5.1.12     
Accepted name: copalyl diphosphate synthase
Reaction: geranylgeranyl diphosphate = (+)-copalyl diphosphate
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.
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. [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. [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. [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. [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. [PMID: 11827528]
[EC 5.5.1.12 created 2002, modified 2012]