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Information on EC 1.14.13.148 - trimethylamine monooxygenase
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1.14.13.148 trimethylamine monooxygenaseIUBMB Comments
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].
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Word Map
- 1.14.13.148
-
1.14.13.8
-
flavin-containing
- trimethylamine-n-oxide
-
fad-containing
-
trimethylaminuria
- methimazole
-
n-oxygenation
- dimethylaniline
-
s-oxidation
- n-octylamine
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Reaction Schemes
Synonyms
flavin monooxygenase 3, trimethylamine monooxygenase, tma monooxygenase, tma n-oxygenase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
dimethyl sulfoxide/trimethylamine N-oxide reductase
-
EC 1.14.13.8
flavin-containing monooxygenase
flavin-containing monooxygenase 3
FMO
FMO3
TMA monooxygenase
TMM
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
N,N,N-trimethylamine + NADPH + H+ + O2 = N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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PATHWAY SOURCE
PATHWAYS
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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].
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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
10-[(N,N-dimethylaminopentyl)]-2-(trifluoromethylphenothiazine) + NADPH + H+ + O2
?
-
functional substrate
-
-
?
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
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
dimethyl sulfide + NADPH + H+ + O2
dimethyl sulfoxide + NADP+ + H2O
-
-
-
?
methimazole + NADPH + H+ + O2
? + NADP+ + H2O
-
-
-
?
methyl 4-tolyl sulfide + NADPH + H+ + O2
methyl 4-tolyl sulfoxide + NADP+ + H2O
-
-
-
-
?
N,N-dimethylaniline + NADPH + H+ + O2
N,N-dimethylaniline N-oxide + NADP+ + H2O
-
-
-
-
?
N,N-dimethylbutylamine + NADPH + H+ + O2
N,N-dimethylbutylamine N-oxide + NADP+ + H2O
-
-
-
-
?
tyramine + NADPH + H+ + O2
4-[(2E)-2-(hydroxyimino)ethyl]phenol + NADP+ + H2O
-
-
-
-
?
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
i.e. 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone
-
-
?
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
-
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
-
-
-
?
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
-
-
-
-
?
benzydamine + NADPH + H+ + O2
benzydamine N-oxide + NADP+ + H2O
-
-
-
-
?
benzydamine + NADPH + H+ + O2
benzydamine N-oxide + NADP+ + H2O
-
-
-
-
?
methimazole + NADPH + H+ + O2
methimazole N-oxide + NADP+ + H2O
-
-
-
?
N,N,N-trimethylamine + NADH + H+ + O2
N,N,N-trimethylamine N-oxide + NAD+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADH + H+ + O2
N,N,N-trimethylamine N-oxide + NAD+ + H2O
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
highest affinity substrate
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
substrate from salmon protein hydrolysate
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
substrate from salmon protein hydrolysate
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
substrate from salmon protein hydrolysate
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
substrate from salmon protein hydrolysate
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N-dimethylamine + NADPH + H+ + O2
N,N-dimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N-dimethylamine + NADPH + H+ + O2
N,N-dimethylamine N-oxide + NADP+ + H2O
-
-
-
?
N,N-dimethylamine + NADPH + H+ + O2
N,N-dimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
sulindac sulfide + NADPH + H+ + O2
sulindac + NADP+ + H2O
-
the enzyme does not display saturability at concentrations through 1 mM of sulindac sulfide
-
-
?
sulindac sulfide + NADPH + H+ + O2
sulindac + NADP+ + H2O
-
the enzyme does not display saturability at concentrations through 1 mM of sulindac sulfide
-
-
?
additional information
?
-
-
no activity with N-monomethylamine, glutathione, and cysteine
-
-
?
additional information
?
-
-
enzyme is capable of oxidizing N,N,N-trimethylamine, in presence of a sufficient amount of NADPH, yielding increased amounts of N,N,N-trimethylamine N-oxide
-
-
-
additional information
?
-
-
enzyme is capable of oxidizing N,N,N-trimethylamine, in presence of a sufficient amount of NADPH, yielding increased amounts of N,N,N-trimethylamine N-oxide
-
-
-
additional information
?
-
enzyme is capable of oxidizing N,N,N-trimethylamine, in presence of a sufficient amount of NADPH, yielding increased amounts of N,N,N-trimethylamine N-oxide
-
-
-
additional information
?
-
-
enzyme is capable of oxidizing N,N,N-trimethylamine, in presence of a sufficient amount of NADPH, yielding increased amounts of N,N,N-trimethylamine N-oxide
-
-
-
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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
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
-
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FAD
FAD and NADPH molecules are essential for the catalysis
NADPH
-
dependent on, in the absence of NADPH the enzyme is rapidly and irreversibly inactivated at 0-5°C. NADP+ also stabilizes the enzyme, but to a lesser extent than NADPH. No oxidation of N,N,N-trimethylamine is observed when NADH is used in the enzyme assay instead of NADPH
NADPH
-
required for activity, in the absence of NADP or NADPH, the FAD-containing monooxygenase is irreversibly inactivated at 37°C during 30 min
NADPH
FAD and NADPH molecules are essential for the catalysis
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3-dimethylaminopropan-1-ol
-
inhibitory at concentrations above about 1 mM
3-dimethylaminopropan-2-ol
-
inhibitory at concentrations above about 1 mM
Cu2+
-
0.2 mM Cu2+ inhibits the enzyme strongly without any preincubation
N,N-dimethyl-2-chloroethylamine
-
inhibitory at concentrations above about 1 mM
N,N-dimethylethanolamine
-
inhibitory at concentrations above about 1 mM
N,N-dimethylethylenediamine
-
inhibitory at concentrations above about 1 mM
N,N-dimethylpropylenediamine
-
inhibitory at concentrations above about 1 mM
N-ethylmaleimide
-
preincubation of the enzyme for 15 min at 14°C, pH 7.7, in the presence of 1.0 mM N-ethylmaleimide inhibits the enzymatic activity approximately by 25%
p-chloromercuribenzoate
-
preincubation of the enzyme for 15 min at 14°C, pH 7.7, in the presence of 0.2 mM p-chloromercuribenzoate inhibits the enzymic activity approximately by 90%
Thiourea
thiourea reduces ethionamide oxygenation to ethionamide S-oxide by an average of 73.5% in liver and 76.9% in lung
additional information
-
the enzyme is not inhibited by CO, cyanide or SKF 525-A (2-diethylaminoethyl 2,2-diphenylvalerate hydrochloride), nor by chelating agents
-
additional information
-
10 mM EDTA, 1 mM potassium cyanide and 1 mM sodium azide do not inhibit the enzyme. Bubbling the enzyme solution with CO for 2 min at 0°C or including CO (CO:O2 ratio 1:1) during the tests has no effect on enzyme activity
-
additional information
-
enzyme reactions are not inhibited by gas phase containing up to 80% carbon monoxide/20% oxygen mixture
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
chlorpromazine
-
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
-
the activity of the native enzyme is increased at 0.05-0.75 mM of imipramine
O2
-
when the oxygen in the enzyme assay mixture is replaced with 100% nitrogen, there is no formation of N,N,N-trimethylamine N-oxide, showing that the enzyme is oxygen-dependent
additional information
n-octylamine has no effect on isoform FMO3
-
additional information
n-octylamine has no effect on isoform FMO3
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Adenoma
Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis.
Adenomatous Polyposis Coli
Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis.
Adenomatous Polyposis Coli
Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis.
Atherosclerosis
Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis.
Atherosclerosis
Trimethylamine-N-oxide: a link between the gut microbiome, bile acid metabolism, and atherosclerosis.
Diabetes Mellitus, Type 2
Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes.
Infections
Selective Modulation of Hepatic Cytochrome P450 and Flavin Monooxygenase 3 Expression during Citrobacter rodentium Infection in Severe Combined Immune-Deficient Mice.
Thrombosis
Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk.
trimethylamine monooxygenase deficiency
Biochemical and molecular studies in mild flavin monooxygenase 3 deficiency.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
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
3.139
cysteamine
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.0357
dimethylaniline
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.0103
Dimethylsulfide
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
3.575
DMSO
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.045
Benzydamine
-
truncated recombinant enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.056
Benzydamine
-
wild type enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.0282
Methimazole
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.03
Methimazole
isoform FMO3, at pH 8.4, temperature not specified in the publication
0.033
Methimazole
-
wild type enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.035
Methimazole
-
truncated recombinant enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.0003
N,N,N-trimethylamine
-
in potassium diphosphate buffer (pH 7.7), at 14°C
0.0094
N,N,N-trimethylamine
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.013 - 0.0548
N,N,N-trimethylamine
-
the Km for isoform FMO3 determined in human liver microsomes ranges from 0.013.to 0.0548 mM, at pH 7.4 and 22°C
0.0208
N,N,N-trimethylamine
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.0216
N,N,N-trimethylamine
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.0275
N,N,N-trimethylamine
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.0285
N,N,N-trimethylamine
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.0897
N,N-dimethylamine
-
recombinant enzyme, in 80 mM PIPES buffer (pH 7.6), at 22°C
0.022
sulindac sulfide
-
truncated recombinant enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.025
sulindac sulfide
-
wild type enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE