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Enzyme Nomenclature
Information on EC 1.14.13.B3 - nicotine demethylase
for references in articles please use BRENDA:EC1.14.13.B3
Word Map on EC 1.14.13.B3
- 1.14.13.B3
- tobacco
- nornicotine
- nicotiana
- tabacum
-
alkaloid
- leaf
-
n-demethylation
-
carcinogen
- n'-nitrosonornicotine
-
tobacco-specific
-
nitrosamine
-
cultivar
- tomentosiformis
-
curing
-
burley
-
undesirable
-
enantioselective
- sylvestris
-
elicitor-induced
-
s-nicotine
- nutrition
-
rnai-induced
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nonconverter
- agriculture
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
1.14.13.B3
preliminary BRENDA-supplied EC number
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RECOMMENDED NAME
GeneOntology No.
nicotine demethylase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
nicotine + NADPH + O2 + H+ = nornicotine + formaldehyde + NADP+ + H2O
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-
-
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SYSTEMATIC NAME
IUBMB Comments
nicotine,NADPH:oxygen oxidoreductase (demethylating)
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CAS REGISTRY NUMBER
COMMENTARY
97162-77-1
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
only microsomes from yeast expressing the D121-AA8 cDNA exhibit significant nicotine demethylase activity
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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)-nicotine + O2 + NADPH + H+
(R)-nornicotine + formaldehyde + NADP+ + H2O
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isoforms CYP82E4, CYP82E5v2, and CYP82E10 demethylate (R)-nicotine 3, 10, and 10fold faster than (S)-nicotine, respectively
-
-
?
nicotine + O2 + NADPH + H+
nornicotine + formaldehyde + NADP+ + H2O
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-
-
-
?
additional information
?
-
-
isoforms CYP2A6 and CYP2B6 significantly contribute to the nicotine N-demethylation at low and high substrate concentrations, respectively
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-
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(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
-
-
-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
-
-
-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
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CYP82E4 selectively demethylates (S)-nicotine
-
-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
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only isoform CYP82E4 can significantly convert (S)-nicotine to (S)-nornicotine
-
-
?
nicotine + NADPH + H+
nornicotine + NADP+ + ?
-
isoform CYP82E4v1 is responsible for the conversion of nicotine to nornicotine
-
?
nicotine + NADPH + H+
nornicotine + NADP+ + ?
nornicotine is a secondary tobacco alkaloid that is produced by the N-demethylation of nicotine. Nornicotine production and accumulation in tobacco are undesirable because nornicotine serves as the precursor in the synthesis of the carcinogen N-nitrosonornicotine during the curing and processing of tobacco
-
-
?
nicotine + NADPH + H+
nornicotine + NADP+ + ?
-
-
-
?
nicotine + NADPH + O2 + H+
nornicotine + formaldehyde + NADP+ + H2O
-
-
-
?
nicotine + NADPH + O2 + H+
nornicotine + formaldehyde + NADP+ + H2O
demethylates nicotine to form nornicotine, a precursor to the nitrosamine N'-nitrosonornicotine
-
-
?
nicotine + NADPH + O2 + H+
nornicotine + formaldehyde + NADP+ + H2O
six putative substrate recognition sites
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-
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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)-nicotine + O2 + NADPH + H+
(R)-nornicotine + formaldehyde + NADP+ + H2O
-
isoforms CYP82E4, CYP82E5v2, and CYP82E10 demethylate (R)-nicotine 3, 10, and 10fold faster than (S)-nicotine, respectively
-
-
?
nicotine + NADPH + O2 + H+
nornicotine + formaldehyde + NADP+ + H2O
Q38Q87
demethylates nicotine to form nornicotine, a precursor to the nitrosamine N'-nitrosonornicotine
-
-
?
nicotine + O2 + NADPH + H+
nornicotine + formaldehyde + NADP+ + H2O
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-
-
-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
J7M2E3, J7M5N9, J7MB22, J7MDR0
-
-
-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
J7M8Q0
-
-
-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
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CYP82E4 selectively demethylates (S)-nicotine
-
-
?
(S)-nicotine + O2 + NADPH + H+
(S)-nornicotine + formaldehyde + NADP+ + H2O
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only isoform CYP82E4 can significantly convert (S)-nicotine to (S)-nornicotine
-
-
?
nicotine + NADPH + H+
nornicotine + NADP+ + ?
Q38Q86
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isoform CYP82E4v1 is responsible for the conversion of nicotine to nornicotine
-
?
nicotine + NADPH + H+
nornicotine + NADP+ + ?
Q38Q86
nornicotine is a secondary tobacco alkaloid that is produced by the N-demethylation of nicotine. Nornicotine production and accumulation in tobacco are undesirable because nornicotine serves as the precursor in the synthesis of the carcinogen N-nitrosonornicotine during the curing and processing of tobacco
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-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Chloropromazine
1 mM, 87% inhibition of recombinant nicotine demethylase activity in yeast microsomes
cytochrome c
1 mM, 78% inhibition of recombinant nicotine demethylase activity in yeast microsomes
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
LITERATURE
IMAGE
additional information
-
no activiation by putrescine, glycine, or ethanolamine
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0203
(S)-nicotine
isoform CYP82E1, in 50 mM Tris-HCl (pH 7.5), at 25°C
0.054
(S)-nicotine
isoform CYP82E2, in 50 mM Tris-HCl (pH 7.5), at 25°C
0.0619
(S)-nicotine
isoform CYP82E4, in 50 mM Tris-HCl (pH 7.5), at 25°C
0.0684
(S)-nicotine
isoform CYP82E1, in 50 mM Tris-HCl (pH 7.5), at 25°C
0.1186
(S)-nicotine
isoform CYP82E3, in 50 mM Tris-HCl (pH 7.5), at 25°C
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
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
high expression in green leaf; high induced during leaf senescence
strong expression; strong expression; strong expression; strong expression
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
putative N-terminal hydrophobic trans-membrane domain
-
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
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Saccharomyces cerevisiae
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C330W
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
C330W
isoform CYP82E3 variant, active; isoform CYP82E3 variant, active
additional information
analysis of polymorphic variations of the CYP82E2 orthologs in Nicotiana sylvestris and various Nicotiana tabacum genotypes
additional information
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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
additional information
-
wild-type isoform CYP82E3 shares 95% predicted amino acid sequence identity with isoform CYP82E4 but conferrs no activity when expressed in yeast or tobacco. Series of domain-swapping experiments between isoforms CYP82E3 and CYP82E4 to isentify regions and amino acids required for catalytic activity
additional information
-
inhibition of gene expression by RNAi leads to up ot sixfold decrease in nornicotine content with concomitant decrease in N'-nitrosonornicotine and total tobacco-specific nitrosamines
additional information
wild-type isoform CYP82E3 shares 95% predicted amino acid sequence identity with isoform CYP82E4 but confers no activity when expressed in yeast or tobacco. Series of domain-swapping experiments between isoforms CYP82E3 and CYP82E4 to identify regions and amino acids required for catalytic activity; wild-type isoform CYP82E3 shares 95% predicted amino acid sequence identity with isoform CYP82E4 but confers no activity when expressed in yeast or tobacco. Series of domain-swapping experiments between isoforms CYP82E3 and CYP82E4 to isentify regions and amino acids required for catalytic activity
additional information
wild-type isoform CYP82E3 shares 95% predicted amino acid sequence identity with isoform CYP82E4 but confers no activity when expressed in yeast or tobacco. Series of domain-swapping experiments between isoforms CYP82E3 and CYP82E4 to identify regions and amino acids required for catalytic activity; wild-type isoform CYP82E3 shares 95% predicted amino acid sequence identity with isoform CYP82E4 but confers no activity when expressed in yeast or tobacco. Series of domain-swapping experiments between isoforms CYP82E3 and CYP82E4 to isentify regions and amino acids required for catalytic activity
additional information
-
wild-type isoform CYP82E3 shares 95% predicted amino acid sequence identity with isoform CYP82E4 but confers no activity when expressed in yeast or tobacco. Series of domain-swapping experiments between isoforms CYP82E3 and CYP82E4 to identify regions and amino acids required for catalytic activity; wild-type isoform CYP82E3 shares 95% predicted amino acid sequence identity with isoform CYP82E4 but confers no activity when expressed in yeast or tobacco. Series of domain-swapping experiments between isoforms CYP82E3 and CYP82E4 to isentify regions and amino acids required for catalytic activity
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
agriculture
-
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
nutrition
-
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
-
inhibition of gene expression by RNAi leads to up ot sixfold decrease in nornicotine content with concomitant decrease in N'-nitrosonornicotine and total tobacco-specific nitrosamines
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