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Information on EC 1.14.11.31 - thebaine 6-O-demethylase
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1.14.11.31 thebaine 6-O-demethylaseIUBMB Comments
Requires Fe2+. Catalyses a step in morphine biosynthesis. The product neopinione spontaneously rearranges to the more stable codeinone. The enzyme also catalyses the 6-O-demethylation of oripavine to morphinone, with lower efficiency.
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Word Map
- 1.14.11.31
- poppy
-
opium
- somniferum
- codeine
-
papaver
-
benzylisoquinoline
-
o-demethylation
- dioxygenases
- acinetobacter
- capsule
-
virus-induced
-
morphinan
-
endophyte
- reticuline
-
non-heme
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
t6odm, thebaine 6-o-demethylase, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
T6ODM
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
thebaine + 2-oxoglutarate + O2 = neopinone + formaldehyde + succinate + CO2
spontaneous conversion of neopinione to codeinone
-
thebaine + 2-oxoglutarate + O2 = neopinone + formaldehyde + succinate + CO2
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
thebaine,2-oxoglutarate:oxygen oxidoreductase (6-O-demethylating)
Requires Fe2+. Catalyses a step in morphine biosynthesis. The product neopinione spontaneously rearranges to the more stable codeinone. The enzyme also catalyses the 6-O-demethylation of oripavine to morphinone, with lower efficiency.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(R,S)-canadine + 2-oxoglutarate + O2
?
-
a protoberberine, 32% of activity with oripavine
-
-
?
(R,S)-tetrahydropalmatine + 2-oxoglutarate + O2
?
-
a protoberberine, O-demethylation, below 1% of activity with oripavine
-
-
?
(R,S)-tetrahydropapaverine + 2-oxoglutarate + O2
?
-
a 1-benzylisoquinoline, O-demethylation, 2.1% of activity with oripavine
-
-
?
allocryptopine + 2-oxoglutarate + O2
?
-
a protopine, O-demethylation, 9.5% of activity with oripavine
-
-
?
cryptopine + 2-oxoglutarate + O2
?
-
a protopine, O-demethylation, below 1% of activity with oripavine
-
-
?
oripavine + 2-oxoglutarate + O2
morphinane + formaldehyde + succinate + CO2
-
-
-
-
?
papaverine + 2-oxoglutarate + O2
?
-
a 1-benzylisoquinoline,O-demethylation, below 1% of activity with oripavine
-
-
?
thebaine + 2-oxoglutarate + O2
codeinone + formaldehyde + succinate + CO2
-
-
-
-
?
oripavine + 2-oxoglutarate + O2
morphinone + formaldehyde + succinate + CO2
-
-
-
-
?
oripavine + 2-oxoglutarate + O2
morphinone + formaldehyde + succinate + CO2
-
a step of morphine biosynthesis
-
-
?
oripavine + 2-oxoglutarate + O2
morphinone + formaldehyde + succinate + CO2
-
alkyl hydroxylation proceeds through a radical mechanism involving an iron-oxo intermediate, followed by the elimination of formaldehyde
-
-
?
thebaine + 2-oxoglutarate + O2
neopinone + formaldehyde + succinate + CO2
-
-
-
-
?
thebaine + 2-oxoglutarate + O2
neopinone + formaldehyde + succinate + CO2
-
a step of morphine biosynthesis
spontaneous conversion to codeinone
-
?
thebaine + 2-oxoglutarate + O2
neopinone + formaldehyde + succinate + CO2
-
85% of the activity with oripavine. Alkyl hydroxylation proceeds through a radical mechanism involving an iron-oxo intermediate, followed by the elimination of formaldehyde
spontaneous conversion to codeinone
-
?
thebaine + 2-oxoglutarate + O2
neopinone + formaldehyde + succinate + CO2
-
a morphinan, 97.2% of activity with oripavine
-
-
?
additional information
?
-
-
no activity with (S)-reticuline, (S)-scoulerine, papaverine, (S)-corytuberine, pavine, salutaridine, noscapine, codeine
-
-
?
additional information
?
-
-
when assayed with a wide range of benzylisoquinoline alkaloids, the enzyme shows efficient dealkylation activities, including regio- and substrate-specific O-demethylation and O,O-demethylenation, substrate specificity, overview. No or poor activity with (S)-reticuline, (S)-isocorydine, (S)-scoulerine, (R,S)-stylopine, berberine, O-demethylcryptopine, protopine, and codeine
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
oripavine + 2-oxoglutarate + O2
morphinane + formaldehyde + succinate + CO2
-
-
-
-
?
thebaine + 2-oxoglutarate + O2
codeinone + formaldehyde + succinate + CO2
-
-
-
-
?
oripavine + 2-oxoglutarate + O2
morphinone + formaldehyde + succinate + CO2
-
-
-
-
?
oripavine + 2-oxoglutarate + O2
morphinone + formaldehyde + succinate + CO2
-
a step of morphine biosynthesis
-
-
?
thebaine + 2-oxoglutarate + O2
neopinone + formaldehyde + succinate + CO2
-
-
-
-
?
thebaine + 2-oxoglutarate + O2
neopinone + formaldehyde + succinate + CO2
-
a step of morphine biosynthesis
spontaneous conversion to codeinone
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
high-morphine varieties (i.e. L, 11 and 40) and a mutant variety (i.e. T) that accumulates high levels of thebaine and oripavine, but lacks morphine and codeine
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
the enzyme belongs to the 2-oxoglutarate/Fe(II)-dependent dioxygenase superfamily
malfunction
-
virus-induced gene silencing of T6ODM in opium poppy efficiently blocks metabolism at thebaine
metabolism
physiological function
-
thebaine 6-O-demethylase catalyzes the antepenultimate step of morphine biosynthesis in opium poppy, but has also roles in the metabolism of protopine, benzo[c]phenanthridine, and rhoeadine alkaloids
metabolism
-
thebaine 6-O-demethylase catalyzes the antepenultimate step of morphine biosynthesis in opium poppy
metabolism
the enzyme-substrate complex of T6ODM has a 1:2 stoichiometry. The key residues responsible for substrate binding are Val128, Glu133, Met150 and Agr219 for the substrate in the distal position, and Asp144, Leu235 and Leu353 for the proximal substrate molecule. Tthe oxo ligand is bound trans to His295 and the enzyme catalyzes hydroxylation of the C6-bound methoxy group according to the established rebound mechanism. The final stage of the demethylation reaction includes deformylation and enol-keton tautomerization steps and is most likely catalyzed by water molecules and takes place in the solvent
metabolism
thebaine binds at the two distinct sites of T6ODM and codeine-3-O-demethylase CODM, EC 1.14.11.31, which determines the precise regioselectivity at C6 and C3 positions of thebaine respectively. Thebaine binds in site II (characteristic due to the presence of Asp313) of T6ODM for C6 selectivity. It binds in site I (characteristic due to the presence of Asp143) of CODM for C3 selectivity. Thebaine forms stable ionic interaction with these aspartate residues via its positively charged tertiary amino group and is further stabilized by the hydrophobic interactions via its B ring. The binding of oxygen to the nonheme iron is followed by the Fe(IV)=O bond flip, yielding an octahedral intermediate. During the decarboxylation reaction process, the C-terminal lid in the enzyme changes from the closed conformation in the 5C coordinate Fe(IV)=O complex to an active open conformation in the 6C coordinate complex
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). DIOX1_PAPSO
364
0
40624
Swiss-Prot
other Location (Reliability: 3)
A0A396GMK1_MEDTR
62
0
6773
TrEMBL
other Location (Reliability: 3)
A0A072UER0_MEDTR
353
0
40116
TrEMBL
other Location (Reliability: 5)
A0A2P6Q562_ROSCH
310
0
35449
TrEMBL
other Location (Reliability: 2)
A0A2G9HXH5_9LAMI
352
0
39543
TrEMBL
other Location (Reliability: 3)
A0A2G9GGH5_9LAMI
355
0
40034
TrEMBL
other Location (Reliability: 4)
A0A396JBY5_MEDTR
384
0
44304
TrEMBL
other Location (Reliability: 5)
A0A072TL01_MEDTR
353
0
39919
TrEMBL
other Location (Reliability: 2)
A0A2G9GVE4_9LAMI
350
0
40260
TrEMBL
other Location (Reliability: 3)
A0A396GMQ9_MEDTR
371
0
42136
TrEMBL
other Location (Reliability: 4)
A0A396GPI6_MEDTR
86
0
9573
TrEMBL
other Location (Reliability: 4)
A0A072TJA3_MEDTR
261
0
29948
TrEMBL
other Location (Reliability: 2)
A0A072UFL7_MEDTR
352
0
40073
TrEMBL
other Location (Reliability: 3)
A0A2P6RV84_ROSCH
301
0
34112
TrEMBL
other Location (Reliability: 4)
A0A2G9GZ15_9LAMI
97
0
11063
TrEMBL
other Location (Reliability: 4)
A0A396JDV8_MEDTR
334
0
38451
TrEMBL
other Location (Reliability: 3)
A0A2G9GHQ2_9LAMI
356
0
39749
TrEMBL
other Location (Reliability: 3)
A0A396GMH7_MEDTR
365
0
41266
TrEMBL
other Location (Reliability: 5)
A0A072U060_MEDTR
370
0
42309
TrEMBL
other Location (Reliability: 4)
A0A072VFZ2_MEDTR
358
0
40386
TrEMBL
other Location (Reliability: 2)
A0A2G9G071_9LAMI
177
0
20294
TrEMBL
other Location (Reliability: 2)
A0A2G9GYU2_9LAMI
358
0
40269
TrEMBL
other Location (Reliability: 2)
A0A396GYS0_MEDTR
457
0
52785
TrEMBL
Secretory Pathway (Reliability: 4)
A0A2G9HXH1_9LAMI
166
0
18652
TrEMBL
other Location (Reliability: 2)
A0A396HYT1_MEDTR
379
0
43699
TrEMBL
Mitochondrion (Reliability: 3)
A0A396GME6_MEDTR
131
0
14765
TrEMBL
other Location (Reliability: 3)
A0A396GUN0_MEDTR
355
0
40376
TrEMBL
other Location (Reliability: 2)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
structures of complexes with 2-oxoglutarate and succinate. Both metal and 2-oxoglutarate binding sites display similarity to other proteins from the 2-oxoglutarate/Fe(II)-dependent dioxygenases family. T6ODM is characterized by an exceptionally large substrate binding cavity, whose volume can partially explain its promiscuity
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
endophyte SM3B (Marmoricola sp.) can enhance enzyme expression by 2.5fold
-
enzyme expression is significantly up-regulated with methyl jasmonate and salicylic acid treatments at 48 h
-
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hagel, J.M.; Facchini, P.J.
Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy.
Nat. Chem. Biol.
6
273-275
2010
Papaver somniferum
brenda
Farrow, S.C.; Facchini, P.J.
Dioxygenases catalyze O-demethylation and O,O-demethylenation with widespread roles in benzylisoquinoline alkaloid metabolism in opium poppy
J. Biol. Chem.
288
28997-29012
2013
Papaver somniferum
brenda
Hashemi, S.; Naghavi, M.
Production and gene expression of morphinan alkaloids in hairy root culture of Papaver orientale L. using abiotic elicitors
Plant Cell
125
31-41
2016
Papaver orientale
-
brenda
Pandey, S.S.; Singh, S.; Babu, C.S.; Shanker, K.; Srivastava, N.K.; Kalra, A.
Endophytes of opium poppy differentially modulate host plant productivity and genes for the biosynthetic pathway of benzylisoquinoline alkaloids
Planta
243
1097-1114
2016
Papaver somniferum
brenda
Singh, W.; Hui, C.; Li, C.; Huang, M.
Thebaine is selectively demethylated by thebaine 6-O-demethylase and codeine-3-O-demethylase at distinct binding sites A computational study
Inorg. Chem.
60
10199-10214
2021
Papaver somniferum (D4N500)
brenda
Kachhap, S.; Wojdyla, Z.; Komorek, P.; Kluza, A.; Kurpiewska, K.; Jachimska, B.; Borowski, T.
It takes two to tango - The case of thebaine 6-O-demethylase
Int. J. Biol. Macromol.
163
718-729
2020
Papaver somniferum (D4N500)
brenda
Kluza, A.; Niedzialkowska, E.; Kurpiewska, K.; Wojdyla, Z.; Quesne, M.; Kot, E.; Porebski, P.J.; Borowski, T.
Crystal structure of thebaine 6-O-demethylase from the morphine biosynthesis pathway
J. Struct. Biol.
202
229-235
2018
Papaver somniferum (D4N500), Papaver somniferum
brenda
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Release 2023.1 (January 2023)
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