Information on EC 1.14.13.148 - trimethylamine monooxygenase and Organism(s) Homo sapiens

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Homo sapiens


The expected taxonomic range for this enzyme is: Bacteria, Eukaryota


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
1.14.13.148
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RECOMMENDED NAME
GeneOntology No.
trimethylamine monooxygenase
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
trimethylamine degradation
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Methane metabolism
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SYSTEMATIC NAME
IUBMB Comments
N,N,N-trimethylamine,NADPH:oxygen oxidoreductase (N-oxide-forming)
A flavoprotein. The bacterial enzyme enables bacteria to use trimethylamine as the sole source of carbon and energy [1,4]. The mammalian enzyme is involved in detoxification of trimethylamine. Mutations in the human enzyme cause the inheritable disease known as trimethylaminuria (fish odor syndrome) [2,3].
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
physiological function
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isozyme FMO3 regulates the conversion of N,N,N-trimethylamine into its N-oxide and hence controls the release of volatile N,N,N-trimethylamine from the individual
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
10-[(N,N-dimethylaminopentyl)]-2-(trifluoromethylphenothiazine) + NADPH + H+ + O2
?
show the reaction diagram
-
functional substrate
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-
?
5-{[3-(dimethylamino)propyl]amino}-8-hydroxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one + NADPH + H+ + O2
5-{[3-(dimethylnitroryl)propyl]amino}-8-hydroxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one + NADP+ + H2O
show the reaction diagram
i.e. 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone
-
-
?
5-{[3-(dimethylamino)propyl]amino}-8-methoxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one + NADPH + H+ + O2
5-{[3-(dimethylnitroryl)propyl]amino}-8-methoxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one + NADP+ + H2O
show the reaction diagram
-
-
-
?
benzydamine + NADPH + H+ + O2
benzydamine N-oxide + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
danusertib + NADPH + H+ + O2
danusertib N-oxide + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
ethionamide + NADPH + H+ + O2
ethionamide S-oxide + NADP+ + H2O
show the reaction diagram
-
-
-
?
methimazole + NADPH + H+ + O2
?
show the reaction diagram
-
-
-
-
?
methimazole + NADPH + H+ + O2
methimazole N-oxide + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
methyl 4-tolyl sulfide + NADPH + H+ + O2
methyl 4-tolyl sulfoxide + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
sulindac sulfide + NADPH + H+ + O2
sulindac + NADP+ + H2O
show the reaction diagram
tozasertib + NADPH + H+ + O2
tozasertib N-oxide + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
tyramine + NADPH + H+ + O2
-
show the reaction diagram
-
-
-
-
?
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
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
show the reaction diagram
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-
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADPH
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Thiourea
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
chlorpromazine
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the activity of the native enzyme is increased at 0.001-0.2 mM of chlorpromazine. Greatest activation is 85% when methimazole and chlorpromazine concentrations are 2 mM and 0.1 mM, respectively
imipramine
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the activity of the native enzyme is increased at 0.05-0.75 mM of imipramine
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.1116
5-{[3-(dimethylamino)propyl]amino}-8-hydroxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one
isozyme FMO3, in 0.1 M potassium phosphate buffer (pH 8.4) at 37°C
0.1624
5-{[3-(dimethylamino)propyl]amino}-8-methoxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one
isozyme FMO3, in 0.1 M potassium phosphate buffer (pH 8.4) at 37°C
0.0426 - 0.056
Benzydamine
0.336
Ethionamide
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isozyme FMO3, at pH 9.5 and 37°C
0.0285 - 0.035
Methimazole
0.013 - 0.0548
N,N,N-trimethylamine
0.022 - 0.0693
sulindac sulfide
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.973
Ethionamide
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isozyme FMO3, at pH 9.5 and 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.049
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crude enzyme from membranes, using methyl 4-tolyl sulfide as substrate, in 25 mM potassium diphosphate (pH 8.5), at 37°C
0.201
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after purification, using methyl 4-tolyl sulfide as substrate, in 25 mM potassium diphosphate (pH 8.5), at 37°C
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4 - 8.4
the activity is approximately twice as high at pH 8.4 as at pH 7.4
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
56000
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x * 56000, SDS-PAGE
60000
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x * 60000, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
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N-linked glycosylation at Asn61 and O-linked glycosylation at Thr29, Thr249, and Thr381. Posttranslational modification of human FMO3 by insect cells is limited to cleavage at the N-terminal methionine
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cholate solubilization and sequential column chromatography on octyl-Sepharose, DEAE-Sepharose, and hydroxyapatite
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DEAE ion exchange column chromatography and Ni affinity column chromatography
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
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expressed in Sf9 insect cells
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expressed in Trichoplusia ni cells and in Escherichia coli strain XL-1 Blue
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expressed in Trichoplusia ni cells using a baculovirus expression vector system
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wild type and truncated enzymes are expressed in Escherichia coli JM109 cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
5-aza-2'-deoxycytidine at 0.001 mM and 0.0025 mM results in 6.6fold and 9.2fold increases in FMO3 mRNA levels, respectively. HNF4alpha transient expression results in a 3.1fold increase in FMO3 mRNA levels. Co-transfection of HepG2 cells with the CCAAT/enhancer-binding protein beta expression vector and the pRNH694 reporter construct results in a dose-dependent increase in FMO3 promoter activity with a maximal 2fold increase using 0.001 mg of expression
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no changes in relative FMO3 mRNA levels are observed with 50 nM trichostatin A
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E24D
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the mutation impacts the structure of the Rossmann fold involved in FAD binding and does not alter FMO3 catalytic activity
E305X
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the mutation is associated with trimethylaminuria
K416N
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the mutation has minimal impact on either hydrophilicity or protein structure
M66I
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the mutation is associated with trimethylaminuria
N245N
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the mutation is associated with trimethylaminuria
N61K
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the mutation disrupts the secondary structure of a conserved membrane interaction domain and does not alter FMO3 catalytic activity
P153L
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the mutation is associated with trimethylaminuria
P153L/E305X
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the mutation is associated with trimethylaminuria
S310S
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the mutation is associated with trimethylaminuria
T428R
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methimazole activity of the mutant enzyme is stimulated (maximally 25% when the methimazole concentration is 2 mM) to the same extend of native enzyme up to an imipramine concentration of 3 mM. The activity of the mutant is inhibited at concentrations above 0.3 mM imipramine, 0.75 mM imipramine causes 93% inhibition of methimazole activity of the mutant enzyme. Chlorpromazine activates the mutant enzyme only at high substrate concentrations (0.1-2 mM)