Information on EC 1.14.13.B3 - nicotine demethylase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.14.13.B3
preliminary BRENDA-supplied EC number
RECOMMENDED NAME
GeneOntology No.
nicotine demethylase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
nicotine + NADPH + O2 + H+ = nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
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SYSTEMATIC NAME
IUBMB Comments
nicotine,NADPH:oxygen oxidoreductase (demethylating)
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CAS REGISTRY NUMBER
COMMENTARY hide
97162-77-1
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
isoform CYP82E2
UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
only microsomes from yeast expressing the D121-AA8 cDNA exhibit significant nicotine demethylase activity
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(R)-nicotine + O2 + NADPH + H+
(R)-nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
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isoforms CYP82E4, CYP82E5v2, and CYP82E10 demethylate (R)-nicotine 3, 10, and 10fold faster than (S)-nicotine, respectively
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-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
nicotine + NADPH + H+
nornicotine + NADP+
show the reaction diagram
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-
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-
?
nicotine + NADPH + H+
nornicotine + NADP+ + ?
show the reaction diagram
nicotine + NADPH + O2 + H+
nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
nicotine + O2 + NADPH + H+
nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
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?
additional information
?
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isoforms CYP2A6 and CYP2B6 significantly contribute to the nicotine N-demethylation at low and high substrate concentrations, respectively
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(R)-nicotine + O2 + NADPH + H+
(R)-nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
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isoforms CYP82E4, CYP82E5v2, and CYP82E10 demethylate (R)-nicotine 3, 10, and 10fold faster than (S)-nicotine, respectively
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-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
nicotine + NADPH + H+
nornicotine + NADP+ + ?
show the reaction diagram
nicotine + NADPH + O2 + H+
nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
Q38Q87
demethylates nicotine to form nornicotine, a precursor to the nitrosamine N'-nitrosonornicotine
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?
nicotine + O2 + NADPH + H+
nornicotine + formaldehyde + NADP+ + H2O
show the reaction diagram
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P450
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NADPH
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Iron
cysteine-containing heme-binding region
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1-aminobenzotriazole
at 1 mM inhibits by 17%
anti-CYP2A6 antibody
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Chloropromazine
1 mM, 87% inhibition of recombinant nicotine demethylase activity in yeast microsomes
chlorpromazine
at 1 mM inhibits by 87%
CO
partial reverse activity after light exposure
coumarin
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cytochrome c
1 mM, 78% inhibition of recombinant nicotine demethylase activity in yeast microsomes
Oxidized cytochrome c
at 0.1 mM inhibits by 78%
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Piperonylbutoxide
at 1 mM inhibits by 42%
additional information
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not inhibitory: quinidine, anti-CYP2D6 serum, ketoconazole, anti-CYP3A4 serum
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
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no activiation by putrescine, glycine, or ethanolamine
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0203 - 0.1186
(S)-nicotine
0.0039 - 0.55
Nicotine
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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nicotine N-demethylase activity in microsomes from human livers at 0.02 mM nicotine is significantly correlated with the isoform CYP2A6 contents, while the nicotine N-demethylase activity at 0.1 mM nicotine is significantly correlated with the isoform CYP2B6 contents
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
putative N-terminal hydrophobic trans-membrane domain
Manually annotated by BRENDA team
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
D121-AA8 cDNA transformed into yeast cells; expression in yeast
expression in Escherichia coli
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expression in Saccharomyces cerevisiae
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
ethylene induces microsomal demethylase activity in leaves
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E375K
loss of catalytic activity
W422L
loss of catalytic activity
K269N
isoform CYP82E3 variant, no catalytic activity; isoform CYP82E3 variant, no catalytic activity
K269N/I274Null
isoform CYP82E3 variant, no catalytic activity; isoform CYP82E3 variant, no catalytic activity
K269N/I274Null/T279A
isoform CYP82E3 variant, no catalytic activity; isoform CYP82E3 variant, no catalytic activity
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
agriculture
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while the nornicotine content of most commercial burley tobacco is low, a process termed conversion can bestow considerably increased nornicotine levels in a portion of the plants within the population. Transcript accumulation of isoform CYP82E4 is enhanced as much as 80fold in converter vs nonconverter tobacco. An optimized RNAi construct 82E4Ri298 suppresses nicotine to nornicotine conversion from 98% to as low as 0.8% in a strong converter tobacco line, a rate of nornicotine production that is about 3.6fold lower than typically detected in commercial varieties. Greenhouse-grown transgenic plants transformed with the RNAi construct are morphologically indistinguishable from the empty vector or wild-type controls
nutrition