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(6S)-6-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
(6S)-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
?
3-hydroxy-3-phenylpropionyltropine + 2-oxoglutarate + O2
3-hydroxy-3-phenylpropionyl-6-hydroxytropine + succinate + CO2 + H2O
-
-
-
?
6,7-dehydrohyoscyamine + 2-oxoglutarate + O2
?
-
-
-
-
?
6,7-dehydrohyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
?
8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(dimethylamino)phenyl)acetate + 2-oxoglutarate + O2
?
-
-
-
-
?
8-methyl-8-azabicyclo[3.2.1]octan-3-yl benzoate + 2-oxoglutarate + O2
?
-
-
-
-
?
apoatropine + 2-oxoglutarate + O2
6-hydroxyapoatropine + succinate + CO2 + H2O
-
-
-
?
l-homatropine + 2-oxoglutarate + O2
6-hydroxyhomatropine + succinate + CO2 + H2O
-
-
-
?
norhyoscyamine + 2-oxoglutarate + O2
6-hydroxynorhyoscyamine + succinate + CO2 + H2O
-
-
-
?
phenylacetyltropine + 2-oxoglutarate + O2
6-hydroxyphenylacetyltropine + succinate + CO2 + H2O
-
-
-
?
t-cinnamoyltropine + 2-oxoglutarate + O2
t-cinnamoyl-6-hydroxytropine + succinate + CO2 + H2O
-
-
-
?
additional information
?
-
(6S)-6-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
?
(6S)-6-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
alkaloid metabolism, scopolamine is formed by oxidative transformation of hyoscyamine in several solanaceous species
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
via 6,7-dehydrohyoscyamine or not, two possible pathways for the epoxidation in the biosynthesis of scopolamine, overview
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
-
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
-
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
the bifunctional enzyme also catalyzes the conversion of L-hyoscyamine to (6S)-hydroxyhyoscyamine, cf. 1.14.11.11
-
-
?
additional information
?
-
enzyme catalyzes both the hydroxylation of hyoscyamine, reaction of EC 1.14.11.11, and the epoxidation of 6beta-hydroxyhyoscyamine to generate scopolamine
-
-
?
additional information
?
-
-
enzyme catalyzes both the hydroxylation of hyoscyamine, reaction of EC 1.14.11.11, and the epoxidation of 6beta-hydroxyhyoscyamine to generate scopolamine
-
-
?
additional information
?
-
-
hyoscyamine 6beta-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, converts L-hyoscyamine to its 6,7-epoxy derivative, scopolamine, in two sequential steps, the enzyme also catalyzes the reaaction of EC 1.14.11.11. 6,7-Dehydrohyoscyamine, a potential precursor for the last step of epoxidation, is an obligatory intermediate in the biosynthesis of scopolamine
-
-
?
additional information
?
-
-
hyoscyamine 6beta-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, converts L-hyoscyamine to its 6,7-epoxy derivative, scopolamine, in two sequential steps. The catalytic efficiency of AbH6H, especially for the second oxidation, is low. The epoxidation step is much slower than the hydroxylation step. Substrate analogues 1-methylpiperidin-4-yl 2-phenylacetate, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-phenylpropanoate, 8-oxabicyclo[3.2.1]octan-3-yl 2-phenylacetate, and 4 are no substrates for the enzyme
-
-
?
additional information
?
-
-
the enzyme also catalyzes the reaaction of EC 1.14.11.11
-
-
?
additional information
?
-
-
enzyme catalyzes both the hydroxylation of hyoscyamine, reaction of EC 1.14.11.11, and the epoxidation of 6beta-hydroxyhyoscyamine to generate scopolamine. Epoxidase activity is low compared to the hydroxylase activity. The binding of the substrates, hyoscyamine and 2-oxoglutarate, to the enzyme induces significant conformational changes
-
-
?
additional information
?
-
enzyme catalyzes both the hydroxylation of hyoscyamine, reaction of EC 1.14.11.11, and the epoxidation of 6beta-hydroxyhyoscyamine to generate scopolamine
-
-
?
additional information
?
-
-
enzyme is able to catalyze hydroxylation, dehydrogenation and in vitro epoxidation reactions all giving scopolamine. Hydroxyl rebound is unlikely to take place during the cyclization reaction and the hydroxylase versus oxidative cyclase activity is correlated with the presence of an exo-hydroxy group having syn-periplanar geometry with respect to the adjacent H atom to be abstracted
-
-
?
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(6S)-6-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
alkaloid metabolism, scopolamine is formed by oxidative transformation of hyoscyamine in several solanaceous species
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2 + H2O
-
-
-
?
(6S)-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
?
6,7-dehydrohyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
?
additional information
?
-
-
hyoscyamine 6beta-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, converts L-hyoscyamine to its 6,7-epoxy derivative, scopolamine, in two sequential steps, the enzyme also catalyzes the reaaction of EC 1.14.11.11. 6,7-Dehydrohyoscyamine, a potential precursor for the last step of epoxidation, is an obligatory intermediate in the biosynthesis of scopolamine
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
-
-
-
?
(6S)-6beta-hydroxyhyoscyamine + 2-oxoglutarate + O2
scopolamine + succinate + CO2
-
via 6,7-dehydrohyoscyamine or not, two possible pathways for the epoxidation in the biosynthesis of scopolamine, overview
-
-
?
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(1R,2R,4S,5S,7s)-7-{[(2S)-3-hydroxy-2-phenylpropanoyl]oxy}-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane
-
slight inhibition by the substrate analogue
1-methylpiperidin-4-yl 2-phenylacetate
-
-
3,4-dihydroxybenzoate
competitive inhibitor with respect to 2-oxoglutarate
6,7-Dehydrohyoscyamine
-
-
8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(dimethylamino)phenyl)acetate
-
-
8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-phenylpropanoate
-
-
8-methyl-8-azabicyclo[3.2.1]octan-3-yl benzoate
-
-
8-oxabicyclo[3.2.1]octan-3-yl 2-phenylacetate
-
-
Ca2+
5 mM, 100% inhibition
Cd2+
0.4 mM, 100% inhibition
Co2+
0.4 mM, 100% inhibition
Fe3+
5 mM, 65% inhibition
Hg2+
0.4 mM, 96% inhibition
Mg2+
5 mM, 14% inhibition
Mn2+
0.4 mM, 95% inhibition
Pyridine 2,4-dicarboxylate
Cu2+
5 mM, 100% inhibition
Cu2+
0.4 mM, 100% inhibition
EDTA
5 mM, 61% inhibition
EDTA
0.1 mM, 67% inhibition
Ni2+
5 mM, 64% inhibition
Ni2+
0.4 mM, 96% inhibition
Pyridine 2,4-dicarboxylate
-
-
Pyridine 2,4-dicarboxylate
competitive inhibitor with respect to 2-oxoglutarate
Zn2+
5 mM, 66% inhibition
Zn2+
0.4 mM, 100% inhibition
additional information
-
synthesis and inhibitory potencies of substrate analogues, overview. No inhibition by substrate analogues 1-methylpiperidin-4-yl 2-phenylacetate, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-phenylpropanoate, and 8-oxabicyclo[3.2.1]octan-3-yl 2-phenylacetate
-
additional information
-
no marked effect on enzyme activity by addition of NAD+, NADH, NADP+, NADPH, ATP + MgSO4, FAD, FMN, pyrroloquinoline quinone, acetyl-CoA, 6,7-dimethyl-5,6,7,8-tetrahydrofolate, phenazine methosulfate, 2,6-dichlorophenolindophenol, cytochrome c and H2O2
-
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evolution
-
the enzyme is a member of the 2-oxoglutarate-dependent dioxygenase family
metabolism
-
hyoscyamine 6beta-hydroxylase catalyzes two consecutive oxidation reactions. The first reaction is the hydroxylation of hyoscyamine to 6beta-hydroxyhyoscyamine, Ec 1.14.11.11, and the second is epoxidation of 6beta-hydroxyhyoscyamine yielding scopolamine, the final metabolite in the tropane alkaloid biosynthetic pathway
metabolism
-
hyoscyamine 6beta-hydroxylase converts hyoscyamine to scopolamine in the last step of scopolamine biosynthetic pathway
metabolism
the enzyme is involved in biosynthesis pathway of tropane alkaloids catalyzing two oxidation steps to form scopolamine from hyoscyamine, overview, cf. EC 1.14.11.11
physiological function
Agrobacterium-mediated expression in non-hyoscyamine-producing Nicotiana tabacum and hyoscyamine-producing Hyoscyamus muticus. Transgenic Nicotiana tabacum hairy roots show a more efficient uptake of hyoscyamine from the culture medium and a higher rate of bioconversion of hyoscyamine to scopolamine than those of Hyoscamus muticus. The secretion of scopolamine in Nicotiana tabacum hairy roots is up to 85% of the total scopolamine being released to the culture medium. Exogenous hyoscyamine also causes changes in nicotine alkaloid accumulation in Nicotiana tabacum hairy roots
physiological function
-
overexpression in hairy roots of Atropa baetica leeds to an altered alkaloid profile in which hyoscyamine is entirely converted into scopolamine. Scopolamine accumulation increases up to 9fold amounting to 5.6 mg per g dry weight
physiological function
root cultures overexpressing the enzyme show remarkably elevated levels of scopolamine and anisodamine. Hyoscyamine 6beta-hydroxylases from both Scopolia lurida and Hyoscyamus niger promote anisodamine production at similar levels in Scopolia lurida root cultures. Hyoscyamus niger hyoscyamine 6beta-hydroxylase overexpressing root cultures have more scopolamine in them than Scopolia lurida hyoscyamine 6beta-hydroxylase-overexpressing root cultures
physiological function
-
root cultures overexpressing the enzyme show remarkably elevated levels of scopolamine and anisodamine. Hyoscyamine 6beta-hydroxylases from both Scopolia lurida and Hyoscyamus niger promote anisodamine production at similar levels in Scopolia lurida root cultures. Hyoscyamus niger hyoscyamine 6beta-hydroxylase overexpressing root cultures have more scopolamine in them than Scopolia lurida hyoscyamine 6beta-hydroxylase-overexpressing root cultures
physiological function
the bifunctional enzyme catalyzes the last two steps in the scopolamine biosynthetic pathway: the hydroxylation of L-hyoscyamine to 6beta-hydroxyhyoscyamine (anisodamine) and its subsequent epoxidation to scopolamine
additional information
-
the nitrogen atom in the tropane ring of L-hyoscyamine plays an important role in substrate recognition. Proposed mechanism of epoxidation catalyzed by H6H, overview
additional information
-
the transcript level of H6H increased under chromium treatment. This treatment also increases hyoscyamine and scopolamine contents, phenotype with decreased the growth parameters (weights and lengths of the plantlets) and chlorophyll contents and increased proline contents, overview
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Hashimoto, T.; Kohno, J.; Yamada, Y.
6beta-hydroxyhyoscyamine epoxidase from cultured roots of Hyoscyamus niger
Phytochemistry
28
1077-1082
1989
Hyoscyamus niger
-
brenda
Li, J.; van Belkum, M.J.; Vederas, J.C.
Functional characterization of recombinant hyoscyamine 6beta-hydroxylase from Atropa belladonna
Bioorg. Med. Chem.
20
4356-4363
2012
Atropa belladonna
brenda
Kai, G.; Liu, Y.; Wang, X.; Yang, S.; Fu, X.; Luo, X.; Liao, P.
Functional identification of hyoscyamine 6beta-hydroxylase from Anisodus acutangulus and overproduction of scopolamine in genetically-engineered Escherichia coli
Biotechnol. Lett.
33
1361-1365
2011
Anisodus acutangulus
brenda
Kai, G.; Zhang, A.; Guo, Y.; Li, L.; Cui, L.; Luo, X.; Liu, C.; Xiao, J.
Enhancing the production of tropane alkaloids in transgenic Anisodus acutangulus hairy root cultures by over-expressing tropinone reductase I and hyoscyamine-6beta-hydroxylase
Mol. Biosyst.
8
2883-2890
2012
Anisodus acutangulus, Anisodus acutangulus (A2IBI0)
brenda
Vakili, B.; Karimi, F.; Sharifi, M.; Behmanesh, M.
Chromium-induced tropane alkaloid production and H6H gene expression in Atropa belladonna L. (Solanaceae) in vitro-propagated plantlets
Plant Physiol. Biochem.
52
98-103
2012
Atropa belladonna
brenda
Cao, Y.D.; He, Y.C.; Li, H.; Kai, G.Y.; Xu, J.H.; Yu, H.L.
Efficient biosynthesis of rare natural product scopolamine using E. coli cells expressing a S14P/K97A mutant of hyoscyamine 6beta-hydroxylase AaH6H
J. Biotechnol.
211
123-129
2015
Anisodus acutangulus (A2IBI0)
brenda
Lan, X.; Zeng, J.; Liu, K.; Zhang, F.; Bai, G.; Chen, M.; Liao, Z.; Huang, L.
Comparison of two hyoscyamine 6beta-hydroxylases in engineering scopolamine biosynthesis in root cultures of Scopolia lurida
Biochem. Biophys. Res. Commun.
497
25-31
2018
Anisodus luridus, Hyoscyamus niger (P24397)
brenda
Zarate, R.; el Jaber-Vazdekis, N.; Medina, B.; Ravelo, A.G.
Tailoring tropane alkaloid accumulation in transgenic hairy roots of Atropa baetica by over-expressing the gene encoding hyoscyamine 6beta-hydroxylase
Biotechnol. Lett.
28
1271-1277
2006
Hyoscyamus niger
brenda
Hashimoto, T.; Yamada, Y.
Purification and characterization of hyoscyamine 6 beta-hydroxylase from root cultures of Hyoscyamus niger L. hydroxylase and epoxidase activities in the enzyme preparation
Eur. J. Biochem.
164
277-285
1987
Hyoscyamus niger (P24397)
brenda
Ushimaru, R.; Ruszczycky, M.W.; Chang, W.C.; Yan, F.; Liu, Y.N.; Liu, H.W.
Substrate conformation correlates with the outcome of hyoscyamine 6beta-hydroxylase catalyzed oxidation reactions
J. Am. Chem. Soc.
140
7433-7436
2018
Hyoscyamus niger
brenda
Kai, G.; Chen, J.; Li, L.; Zhou, G.; Zhou, L.; Zhang, L.; Chen, Y.; Zhao, L.
Molecular cloning and characterization of a new cDNA encoding hyoscyamine 6beta-hydroxylase from roots of Anisodus acutangulus
J. Biochem. Mol. Biol.
40
715-722
2007
Anisodus acutangulus (A2IBI0), Anisodus acutangulus
brenda
Haekkinen, S.T.; Moyano, E.; Cusido, R.M.; Palazon, J.; Pinol, M.T.; Oksman-Caldentey, K.M.
Enhanced secretion of tropane alkaloids in Nicotiana tabacum hairy roots expressing heterologous hyoscyamine-6beta-hydroxylase
J. Exp. Bot.
56
2611-2618
2005
Hyoscyamus niger (P24397), Hyoscyamus niger
brenda
Suzuki, K.; Yun, D.J.; Chen, X.Y.; Yamada, Y.; Hashimoto, T.
An Atropa belladonna hyoscyamine 6beta-hydroxylase gene is differentially expressed in the root pericycle and anthers
Plant Mol. Biol.
40
141-152
1999
Atropa belladonna (Q9XJ43), Atropa belladonna
brenda
Pramod, K.K.; Singh, S.; Jayabaskaran, C.
Biochemical and structural characterization of recombinant hyoscyamine 6beta-hydroxylase from Datura metel L
Plant Physiol. Biochem.
48
966-970
2010
Datura metel
brenda
Liu, T.; Zhu, P.; Cheng, K.D.; Meng, C.; He, H.X.
Molecular cloning, expression and characterization of hyoscyamine 6beta-hydroxylase from hairy roots of Anisodus tanguticus
Planta Med.
71
249-253
2005
Anisodus tanguticus (Q6V0J1), Anisodus tanguticus
brenda
Schlesinger, D.; Davidovich Rikanati, R.; Volis, S.; Faigenboim, A.; Vendramin, V.; Cattonaro, F.; Hooper, M.; Oren, E.; Taylor, M.; Sitrit, Y.; Inbar, M.; Lewinsohn, E.
Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6beta-hydroxylase gene
Plant Sci.
283
301-310
2019
Mandragora officinarum (A0A6M6R352)
brenda