ExplorEnz: EC 5.5.1.*

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:

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]

5.5.1.17

Accepted name:

(S)-β-macrocarpene synthase

Reaction:

(S)-β-bisabolene = (S)-β-macrocarpene

For diagram of biosynthesis of bicyclic sesquiterpenoids derived from bisabolyl cation, click here and for diagram of bisabolene and macrocarpene biosynthesis, click here

Other name(s):

TPS6; TPS11; (S)-β-macrocarpene lyase (decyclizing)

Systematic name:

(S)-β-macrocarpene lyase (ring-opening)

Comments:

The synthesis of (S)-β-macrocarpene from (2E,6E)-farnesyl diphosphate proceeds in two steps. The first step is the cyclization to (S)-β-bisabolene (cf. EC 4.2.3.55, (S)-β-bisabolene synthase). The second step is the isomerization to (S)-β-macrocarpene.

Links to other databases:

References:

Kollner, T.G., Schnee, C., Li, S., Svatos, A., Schneider, B., Gershenzon, J. and Degenhardt, J. Protonation of a neutral (S)-β-bisabolene intermediate is involved in (S)-β-macrocarpene formation by the maize sesquiterpene synthases TPS6 and TPS11. J. Biol. Chem. 283 (2008) 20779–20788. [DOI] [PMID: 18524777]

[EC 5.5.1.17 created 2011]

5.5.1.18

Accepted name:

lycopene ε-cyclase

Reaction:

carotenoid ψ-end group = carotenoid ε-end group

For diagram of α-, β-, γ-, δ- and ε-carotene biosynthesis, click here and for diagram of reaction, click here

Other name(s):

CrtL-e; LCYe; carotenoid ψ-end group lyase (decyclizing)

Systematic name:

carotenoid ψ-end group lyase (ring-opening)

Comments:

The carotenoid lycopene has the ψ-end group at both ends. When acting on one end, this enzyme forms δ-carotene. When acting on both ends, it forms ε-carotene.

Links to other databases:

References:

1.	Cunningham, F.X., Jr. and Gantt, E. One ring or two? Determination of ring number in carotenoids by lycopene ε-cyclases. Proc. Natl. Acad. Sci. USA 98 (2001) 2905–2910. [DOI] [PMID: 11226339]
2.	Stickforth, P., Steiger, S., Hess, W.R. and Sandmann, G. A novel type of lycopene ε-cyclase in the marine cyanobacterium Prochlorococcus marinus MED4. Arch. Microbiol. 179 (2003) 409–415. [DOI] [PMID: 12712234]

[EC 5.5.1.18 created 2011]

5.5.1.19

Accepted name:

lycopene β-cyclase

Reaction:

carotenoid ψ-end group = carotenoid β-end group

For diagram of α-, β-, γ-, δ- and ε-carotene biosynthesis, click here, for diagram of reaction, click here and for diagram of 5.5.1.19, click here

Other name(s):

CrtL; CrtL-b; CrtY; LCYb; carotenoid β-end group lyase (decyclizing)

Systematic name:

carotenoid β-end group lyase (ring-opening)

Comments:

The enzyme is a non-redox flavoprotein, containing FADH₂ that is used for stabilization of a transition state. Lycopene has a ψ-end group at both ends. When acting on one end, the enzyme forms γ-carotene. When acting on both ends it forms β-carotene. It also acts on neurosporene to give β-zeacarotene.

Links to other databases:

BRENDA, EXPASY, Gene, KEGG, MetaCyc, CAS registry number: 220801-82-1

References:

1.	Cunningham, F.X., Jr., Chamovitz, D., Misawa, N., Gantt, E. and Hirschberg, J. Cloning and functional expression in Escherichia coli of a cyanobacterial gene for lycopene cyclase, the enzyme that catalyzes the biosynthesis of β-carotene. FEBS Lett. 328 (1993) 130–138. [DOI] [PMID: 8344419]
2.	Cunningham, F.X., Jr., Sun, Z., Chamovitz, D., Hirschberg, J. and Gantt, E. Molecular structure and enzymatic function of lycopene cyclase from the cyanobacterium Synechococcus sp strain PCC7942. Plant Cell 6 (1994) 1107–1121. [DOI] [PMID: 7919981]
3.	Hugueney, P., Badillo, A., Chen, H.C., Klein, A., Hirschberg, J., Camara, B. and Kuntz, M. Metabolism of cyclic carotenoids: a model for the alteration of this biosynthetic pathway in Capsicum annuum chromoplasts. Plant J. 8 (1995) 417–424. [DOI] [PMID: 7550379]
4.	Pecker, I., Gabbay, R., Cunningham, F.X., Jr. and Hirschberg, J. Cloning and characterization of the cDNA for lycopene β-cyclase from tomato reveals decrease in its expression during fruit ripening. Plant Mol. Biol. 30 (1996) 807–819. [PMID: 8624411]
5.	Hornero-Mendez, D. and Britton, G. Involvement of NADPH in the cyclization reaction of carotenoid biosynthesis. FEBS Lett. 515 (2002) 133–136. [DOI] [PMID: 11943208]
6.	Maresca, J.A., Graham, J.E., Wu, M., Eisen, J.A. and Bryant, D.A. Identification of a fourth family of lycopene cyclases in photosynthetic bacteria. Proc. Natl. Acad. Sci. USA 104 (2007) 11784–11789. [DOI] [PMID: 17606904]
7.	Yu, Q., Schaub, P., Ghisla, S., Al-Babili, S., Krieger-Liszkay, A. and Beyer, P. The lycopene cyclase CrtY from Pantoea ananatis (formerly Erwinia uredovora) catalyzes an FADred-dependent non-redox reaction. J. Biol. Chem. 285 (2010) 12109–12120. [DOI] [PMID: 20178989]

[EC 5.5.1.19 created 2011]

5.5.1.20

Accepted name:

prosolanapyrone-III cycloisomerase

Reaction:

prosolanapyrone III = (–)-solanapyrone A

For diagram of solanapyrone biosynthesis, click here

Glossary:

prosolanapyrone III = 4-methoxy-2-oxo-6-(1E,7E,9E)-undeca-1,7,9-trien-1-yl-2H-pyran-3-carboxaldehyde
(–)-solanapyrone A = 4-methoxy-6-((1R,2S,4aR,8aR)-2-methyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-2-oxo-2H-pyran-3-carboxaldehyde

Other name(s):

Sol5 (ambiguous); SPS (ambiguous); solanapyrone synthase (bifunctional enzyme: prosolanapyrone II oxidase/prosolanapyrone III cyclosiomerase)

Systematic name:

prosolanapyrone-III:(–)-solanapyrone A isomerase

Comments:

The enzyme is involved in the biosynthesis of the phytotoxin solanapyrone in some fungi. The bifunctional enzyme catalyses the oxidation of prosolanapyrone II and the subsequent Diels Alder cycloisomerization of the product prosolanapyrone III to (–)-solanapyrone A (cf. EC 1.1.3.42, prosolanapyrone II oxidase).

Links to other databases:

References:

1.	Kasahara, K., Miyamoto, T., Fujimoto, T., Oguri, H., Tokiwano, T., Oikawa, H., Ebizuka, Y. and Fujii, I. Solanapyrone synthase, a possible Diels-Alderase and iterative type I polyketide synthase encoded in a biosynthetic gene cluster from Alternaria solani. ChemBioChem 11 (2010) 1245–1252. [DOI] [PMID: 20486243]
2.	Katayama, K., Kobayashi, T., Oikawa, H., Honma, M. and Ichihara, A. Enzymatic activity and partial purification of solanapyrone synthase: first enzyme catalyzing Diels-Alder reaction. Biochim. Biophys. Acta 1384 (1998) 387–395. [DOI] [PMID: 9659400]
3.	Katayama, K., Kobayashi, T., Chijimatsu, M., Ichihara, A. and Oikawa, H. Purification and N-terminal amino acid sequence of solanapyrone synthase, a natural Diels-Alderase from Alternaria solani. Biosci. Biotechnol. Biochem. 72 (2008) 604–607. [DOI] [PMID: 18256508]

[EC 5.5.1.20 created 2011]

5.5.1.21

Transferred entry:

copal-8-ol diphosphate synthase. The enzyme was discovered at the public-review stage to have been misclassified and so was withdrawn. See EC 4.2.1.133, copal-8-ol diphosphate hydratase

[EC 5.5.1.21 created 2012, deleted 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]

5.5.1.23

Accepted name:

aklanonic acid methyl ester cyclase

Reaction:

aklaviketone = methyl aklanonate

For diagram of aklavinone biosynthesis, click here

Glossary:

aklaviketone = methyl (1R,2R)-2-ethyl-2,5,7-trihydroxy-4,6,11-trioxo-1,2,3,4,6,11-hexahydrotetracene-1-carboxylate
methyl aklanonate = methyl [4,5-dihydroxy-9,10-dioxo-3-(3-oxopentanoyl)-9,10-dihydroanthracen-2-yl]acetate

Other name(s):

dauD (gene name); aknH (gene name); dnrD (gene name); methyl aklanonate cyclase; methyl aklanonate-aklaviketone isomerase (cyclizing); aklaviketone lyase (decyclizing)

Systematic name:

aklaviketone lyase (ring-opening)

Comments:

The enzyme is involved in the biosynthesis of aklaviketone, an intermediate in the biosynthetic pathways leading to formation of several anthracycline antibiotics, including aclacinomycin, daunorubicin and doxorubicin.

Links to other databases:

References:

1.	Dickens, M.L., Ye, J. and Strohl, W.R. Analysis of clustered genes encoding both early and late steps in daunomycin biosynthesis by Streptomyces sp. strain C5. J. Bacteriol. 177 (1995) 536–543. [DOI] [PMID: 7836284]
2.	Kendrew, S.G., Katayama, K., Deutsch, E., Madduri, K. and Hutchinson, C.R. DnrD cyclase involved in the biosynthesis of doxorubicin: purification and characterization of the recombinant enzyme. Biochemistry 38 (1999) 4794–4799. [DOI] [PMID: 10200167]
3.	Kallio, P., Sultana, A., Niemi, J., Mantsala, P. and Schneider, G. Crystal structure of the polyketide cyclase AknH with bound substrate and product analogue: implications for catalytic mechanism and product stereoselectivity. J. Mol. Biol. 357 (2006) 210–220. [DOI] [PMID: 16414075]

[EC 5.5.1.23 created 2013, modified 2014]

5.5.1.24

Accepted name:

tocopherol cyclase

Reaction:

(1) δ-tocopherol = 2-methyl-6-phytylbenzene-1,4-diol
(2) γ-tocopherol = 2,3-dimethyl-6-phytylbenzene-1,4-diol
(3) δ-tocotrienol = 6-geranylgeranyl-2-methylbenzene-1,4-diol
(4) γ-tocotrienol = 6-geranylgeranyl-2,3-dimethylbenzene-1,4-diol

For diagram of tocopherol biosynthesis, click here and for diagram of tocotrienol biosynthesis, click here

Other name(s):

VTE1 (gene name); SXD1 (gene name); δ/γ-tocopherol lyase (decyclizing)

Systematic name:

δ/γ-tocopherol lyase (ring-opening)

Comments:

The enzyme has been described from plants and cyanobacteria. It has similar activity with all four listed benzoquinol substrates. Involved in the biosynthesis of vitamin E (tocopherols and tocotrienols).

Links to other databases:

References:

1.	Porfirova, S., Bergmuller, E., Tropf, S., Lemke, R. and Dormann, P. Isolation of an Arabidopsis mutant lacking vitamin E and identification of a cyclase essential for all tocopherol biosynthesis. Proc. Natl. Acad. Sci. USA 99 (2002) 12495–12500. [DOI] [PMID: 12213958]
2.	Sattler, S.E., Cahoon, E.B., Coughlan, S.J. and DellaPenna, D. Characterization of tocopherol cyclases from higher plants and cyanobacteria. Evolutionary implications for tocopherol synthesis and function. Plant Physiol. 132 (2003) 2184–2195. [DOI] [PMID: 12913173]

[EC 5.5.1.24 created 2013]

5.5.1.25

Accepted name:

3,6-anhydro-L-galactonate cycloisomerase

Reaction:

3,6-anhydro-L-galactonate = 2-dehydro-3-deoxy-L-galactonate

Other name(s):

3,6-anhydro-α-L-galactonate lyase (ring-opening); 3,6-anhydro-α-L-galactonate cycloisomerase

Systematic name:

3,6-anhydro-L-galactonate lyase (ring-opening)

Comments:

The enzyme, characterized from the marine bacteria Vibrio sp. EJY3 and Postechiella marina M091, is involved in a degradation pathway for 3,6-anhydro-α-L-galactopyranose, a major component of the polysaccharides of red macroalgae.

Links to other databases:

BRENDA, EXPASY, Gene, KEGG, MetaCyc, PDB

References:

1.	Yun, E.J., Lee, S., Kim, H.T., Pelton, J.G., Kim, S., Ko, H.J., Choi, I.G. and Kim, K.H. The novel catabolic pathway of 3,6-anhydro-L-galactose, the main component of red macroalgae, in a marine bacterium. Environ. Microbiol. 17 (2015) 1677–1688. [DOI] [PMID: 25156229]
2.	Lee, S.B., Cho, S.J., Kim, J.A., Lee, S.Y., Kim, S.M. and Lim, H.S. Metabolic pathway of 3,6-anhydro-L-galactose in agar-degrading microorganisms. Biotechnol. Bioprocess Eng. 19 (2014) 866–878.

[EC 5.5.1.25 created 2014, modified 2015]

5.5.1.26

Accepted name:

nogalonic acid methyl ester cyclase

Reaction:

nogalaviketone = methyl nogalonate

Glossary:

methyl nogalonate = methyl [4,5-dihydroxy-9,10-dioxo-3-(3-oxobutanoyl)-9,10-dihydroanthracen-2-yl]acetate
nogalaviketone = methyl 5,7-dihydroxy-2-methyl-4,6,11-trioxo-3,4,6,11-tetrahydrotetracene-1-carboxylate

Other name(s):

methyl nogalonate cyclase; SnoaL (gene name); methyl nogalonate lyase (cyclizing)

Systematic name:

nogalaviketone lyase (ring-opening)

Comments:

The enzyme, characterized from the bacterium Streptomyces nogalater, is involved in the biosynthesis of the aromatic polyketide nogalamycin.

Links to other databases:

References:

1.	Sultana, A., Kallio, P., Jansson, A., Wang, J.S., Niemi, J., Mantsala, P. and Schneider, G. Structure of the polyketide cyclase SnoaL reveals a novel mechanism for enzymatic aldol condensation. EMBO J. 23 (2004) 1911–1921. [DOI] [PMID: 15071504]
2.	Sultana, A., Kallio, P., Jansson, A., Niemi, J., Mantsala, P. and Schneider, G. Crystallization and preliminary crystallographic data of SnoaL, a polyketide cyclase in nogalamycin biosynthesis. Acta Crystallogr. D Biol. Crystallogr. 60 (2004) 1118–1120. [DOI] [PMID: 15159574]

[EC 5.5.1.26 created 2015]

5.5.1.27

Accepted name:

D-galactarolactone cycloisomerase

Reaction:

(1) D-galactaro-1,4-lactone = 5-dehydro-4-deoxy-D-glucarate
(2) D-glucaro-1,4-lactone = 5-dehydro-4-deoxy-D-glucarate

Other name(s):

GCI

Systematic name:

D-galactaro-1,4-lactone lyase (ring-opening)

Comments:

The enzyme, characterized from the bacterium Agrobacterium fabrum strain C58, is involved in degradation of D-galacturonate and D-glucuronate. Activity with D-galactaro-1,4-lactone is 4-fold higher than with D-glucaro-1,4-lactone.

Links to other databases:

BRENDA, EXPASY, Gene, KEGG, MetaCyc, PDB

References:

1.	Andberg, M., Maaheimo, H., Boer, H., Penttila, M., Koivula, A. and Richard, P. Characterization of a novel Agrobacterium tumefaciens galactarolactone cycloisomerase enzyme for direct conversion of D-galactarolactone to 3-deoxy-2-keto-L-threo-hexarate. J. Biol. Chem. 287 (2012) 17662–17671. [DOI] [PMID: 22493433]
2.	Bouvier, J.T., Groninger-Poe, F.P., Vetting, M., Almo, S.C. and Gerlt, J.A. Galactaro δ-lactone isomerase: lactone isomerization by a member of the amidohydrolase superfamily. Biochemistry 53 (2014) 614–616. [DOI] [PMID: 24450804]

[EC 5.5.1.27 created 2015]

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:

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:

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:

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]

5.5.1.31

Accepted name:

hapalindole H synthase

Reaction:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole = hapalindole H

For diagram of Hapalindole/Fischerindole biosynthesis, click here

Glossary:

hapalindole H = (6aR,9R,10R,10aR)-9-ethenyl-1-isocyano-6,6,9-trimethyl-2,6,6a,7,8,9,10,10a-decahydronaphtho[1,2,3-cd]indole

Other name(s):

famC2 (gene name); famC3 (gene name)

Systematic name:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole cyclase (hapalindole H-forming)

Comments:

The enzyme, characterized from the cyanobacterium Fischerella ambigua UTEX 1903, forms the core structure of the hapalindole family of alkaloids. The enzyme is a heterodimeric complex.

Links to other databases:

References:

1.	Li, S., Lowell, A.N., Newmister, S.A., Yu, F., Williams, R.M. and Sherman, D.H. Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids. Nat. Chem. Biol. 13 (2017) 467–469. [DOI] [PMID: 28288107]

[EC 5.5.1.31 created 2018]

5.5.1.32

Accepted name:

12-epi-hapalindole U synthase

Reaction:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole = 12-epi-hapalindole U

For diagram of Hapalindole/Fischerindole biosynthesis, click here

Glossary:

12-epi-hapalindole H = (6aR,9S,10R,10aR)-9-ethenyl-1-isocyano-6,6,9-trimethyl-2,6,6a,7,8,9,10,10a-decahydronaphtho[1,2,3-cd]indole

Other name(s):

famC1 (gene name); HpiC1 (gene name)

Systematic name:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole cyclase (12-epi-hapalindole U-forming)

Comments:

The enzyme, characterized from the cyanobacterium Fischerella ambigua UTEX 1903, forms the core structure of the 12-epi-hapalindole family of alkaloids.

Links to other databases:

References:

1.	Li, S., Lowell, A.N., Yu, F., Raveh, A., Newmister, S.A., Bair, N., Schaub, J.M., Williams, R.M. and Sherman, D.H. Hapalindole/ambiguine biogenesis Is mediated by a Cope rearrangement, C-C bond-forming cascade. J. Am. Chem. Soc. 137 (2015) 15366–15369. [DOI] [PMID: 26629885]

[EC 5.5.1.32 created 2018]

5.5.1.33

Accepted name:

12-epi-fischerindole U synthase

Reaction:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole = 12-epi-fischerindole U

For diagram of Hapalindole/Fischerindole biosynthesis, click here

Glossary:

12-epi-fischerindole U = (6aS,9S,10R,10aS)-9-ethenyl-10-isocyano-6,6,9-trimethyl-5H,6aH,7H,8H,10H,10aH-indeno[2,1-b]indole

Other name(s):

fisC (gene name); fimC5 (gene name)

Systematic name:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole cyclase (12-epi-fischerindole U-forming)

Comments:

The enzyme, characterized from multiple species of the cyanobacterial genus Fischerella, participates in the biosynthesis of the terpenoid indole alkaloids 12-epi-fischerindoles.

Links to other databases:

References:

1.	Li, S., Lowell, A.N., Newmister, S.A., Yu, F., Williams, R.M. and Sherman, D.H. Decoding cyclase-dependent assembly of hapalindole and fischerindole alkaloids. Nat. Chem. Biol. 13 (2017) 467–469. [DOI] [PMID: 28288107]

[EC 5.5.1.33 created 2018]

5.5.1.34

Accepted name:

(+)-cis,trans-nepetalactol synthase

Reaction:

(S)-8-oxocitronellyl enol = (+)-cis,trans-nepetalactol

For diagram of secologanin biosynthesis, click here

Glossary:

(S)-8-oxocitronellyl enol = (2E,6S,7E)-8-hydroxy-2,6-dimethylocta-2,7-dienal
(+)-cis,trans-nepetalactol = (+)-iridodial lactol = (4aS,7S,7aR)-4,7-dimethyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-1-ol

Other name(s):

NEPS1 (gene name); NEPS2 (gene name)

Systematic name:

(S)-8-oxocitronellyl enol cyclase [(+)-cis,trans-nepetalactol-forming]

Comments:

The enzyme, characterized from the plant Nepeta mussinii, binds an NAD⁺ cofactor. The product is a precursor of (+)-cis,trans-nepetalactone, the primary ingredient responsible for the psychoactive effects catnip has on cats.

Links to other databases:

References:

1.	Lichman, B.R., Kamileen, M.O., Titchiner, G.R., Saalbach, G., Stevenson, C.EM., Lawson, D.M. and O'Connor, S.E. Uncoupled activation and cyclization in catmint reductive terpenoid biosynthesis. Nat. Chem. Biol. 15 (2019) 71–79. [PMID: 30531909]
2.	Lichman, B.R., O'Connor, S.E. and Kries, H. Biocatalytic strategies towards [4+2] cycloadditions. Chemistry 25 (2019) 6864–6877. [PMID: 30664302]

[EC 5.5.1.34 created 2019]

5.5.1.35

Accepted name:

(+)-cis,cis-nepetalactol synthase

Reaction:

(S)-8-oxocitronellyl enol = (+)-cis,cis-nepetalactol

For diagram of secologanin biosynthesis, click here

Glossary:

(S)-8-oxocitronellyl enol = (2E,6S,7E)-8-hydroxy-2,6-dimethylocta-2,7-dienal
(+)-cis,cis-nepetalactol =(4aR,7S,7aS)-4,7-dimethyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-1-ol

Other name(s):

NEPS3 (gene name)

Systematic name:

(S)-8-oxocitronellyl enol cyclase [(+)-cis,cis-nepetalactol-forming]

Comments:

The enzyme, characterized from the plant Nepeta mussinii, binds an NAD⁺ cofactor. The product is a precursor of (+)-cis,cis-nepetalactone, one of the stereoisomers responsible for the psychoactive effects catnip has on cats.

Links to other databases:

References:

1.	Lichman, B.R., Kamileen, M.O., Titchiner, G.R., Saalbach, G., Stevenson, C.EM., Lawson, D.M. and O'Connor, S.E. Uncoupled activation and cyclization in catmint reductive terpenoid biosynthesis. Nat. Chem. Biol. 15 (2019) 71–79. [PMID: 30531909]
2.	Lichman, B.R., O'Connor, S.E. and Kries, H. Biocatalytic strategies towards [4+2] cycloadditions. Chemistry 25 (2019) 6864–6877. [PMID: 30664302]

[EC 5.5.1.35 created 2019]

5.5.1.36

Accepted name:

hapalindole U synthase

Reaction:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole = hapalindole U

For diagram of Hapalindole/Fischerindole biosynthesis, click here

Glossary:

hapalindole U = (6aS,9R,10R,10aS)-10-isocyano-6,6,9-trimethyl-9-vinyl-2,6,6a,7,8,9,10,10a-octahydronaphtho[1,2,3-cd]indole

Other name(s):

ambU1/ambU4 (gene names); famC4/famC1 (gene names)

Systematic name:

3-geranyl-3-[(Z)-2-isocyanoethenyl]-1H-indole cyclase (hapalindole U-forming)

Comments:

Requires Ca²⁺. The enzyme, which belongs to the Stig cyclases, has been characterized from multiple species of the cyanobacterial genera Fischerella and Westiellopsis. Stig cyclases catalyse a three step process including a Cope rearrangement, 6-exo-trig cyclization and electrophilic aromatic substitution. The enzyme is a heterodimer of two different proteins (AmbU1 and AmbU4). On their own, AmbU1 catalyses a different reaction, producing 12-epi-hapalindole U (cf. EC 5.5.1.32, 12-epi-hapalindole U synthase) while AmbU4 appears to be inactive. Formation of hapalindole U leads to the biosynthesis of additional terpenoid indole alkaloids such as hapalindole G, ambiguine H, and ambiguine A.

Links to other databases:

References:

1.	Zhu, Q. and Liu, X. Discovery of a calcium-dependent enzymatic cascade for the selective assembly of hapalindole-type alkaloids: on the biosynthetic origin of hapalindole U. Angew. Chem. Int. Ed. Engl. 56 (2017) 9062–9066. [DOI] [PMID: 28626997]
2.	Li, S., Newmister, S.A., Lowell, A.N., Zi, J., Chappell, C.R., Yu, F., Hohlman, R.M., Orjala, J., Williams, R.M. and Sherman, D.H. Control of stereoselectivity in diverse hapalindole metabolites is mediated by cofactor-induced combinatorial pairing of stig cyclases. Angew. Chem. Int. Ed. Engl. 59 (2020) 8166–8172. [DOI] [PMID: 32052896]

[EC 5.5.1.36 created 2024]

5.5.1.37

Accepted name:

catharanthine synthase

Reaction:

dehydrosecodine = catharanthine

For diagram of mechanism, click here and for diagram of biosythesis of stemmadenine and related alkaloids, click here

Other name(s):

CS (gene name)

Systematic name:

dehydrosecodine cyclase (catharanthine-forming)

Comments:

The enzyme, characterized from the plant Catharanthus roseus (Madagascar periwinkle), is a carboxylesterase-like cyclase that catalyses a regio- and enantiodivergent [4+2] cycloaddition reaction to generate the iboga scaffold of catharanthine. cf. EC 5.5.1.38, tabersonine synthase.

Links to other databases:

References:

1.	Caputi, L., Franke, J., Farrow, S.C., Chung, K., Payne, R.ME., Nguyen, T.D., Dang, T.T., Soares Teto Carqueijeiro, I., Koudounas, K., Duge de Bernonville, T., Ameyaw, B., Jones, D.M., Vieira, I.JC., Courdavault, V. and O'Connor, S.E. Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle. Science 360 (2018) 1235–1239. [DOI] [PMID: 29724909]
2.	DeMars, M.D., 2nd and O'Connor, S.E. Evolution and diversification of carboxylesterase-like [4+2] cyclases in aspidosperma and iboga alkaloid biosynthesis. Proc. Natl. Acad. Sci. USA 121:e2318586121 (2024). [DOI] [PMID: 38319969]

[EC 5.5.1.37 created 2024]

5.5.1.38

Accepted name:

tabersonine synthase

Reaction:

dehydrosecodine = tabersonine

For diagram of mechanism, click here and for diagram of biosythesis of stemmadenine and related alkaloids, click here

Other name(s):

TS (gene name)

Systematic name:

dehydrosecodine cyclase (tabersonine-forming)

Comments:

The enzyme, characterized from the plant Catharanthus roseus (Madagascar periwinkle), is a carboxylesterase-like cyclase that catalyses a regio- and enantiodivergent [4+2] cycloaddition reaction to generate the aspidosperma scaffold of tabersonine. cf. EC 5.5.1.37, catharanthine synthase.

Links to other databases: