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EC Tree
IUBMB 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].
The taxonomic range for the selected organisms is: Homo sapiens The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
flavin monooxygenase 3, trimethylamine monooxygenase, tma monooxygenase, tma n-oxygenase,
more
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flavin-containing monooxygenase
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flavin-containing monooxygenase 3
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EC 1.14.13.8
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assigned to
flavin containing monooxygenase 3
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flavin monooxygenase 3
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flavin-containing monooxygenase
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flavin-containing monooxygenase 3
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FMO3
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FMO3
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FMO3
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most active isoform
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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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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
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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
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ethionamide + NADPH + H+ + O2
ethionamide S-oxide + NADP+ + H2O
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N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
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10-[(N,N-dimethylaminopentyl)]-2-(trifluoromethylphenothiazine) + NADPH + H+ + O2
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functional substrate
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benzydamine + NADPH + H+ + O2
benzydamine N-oxide + NADP+ + H2O
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danusertib + NADPH + H+ + O2
danusertib N-oxide + NADP+ + H2O
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methimazole + NADPH + H+ + O2
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methimazole + NADPH + H+ + O2
methimazole N-oxide + NADP+ + H2O
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methyl 4-tolyl sulfide + NADPH + H+ + O2
methyl 4-tolyl sulfoxide + NADP+ + H2O
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N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
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sulindac sulfide + NADPH + H+ + O2
sulindac + NADP+ + H2O
tozasertib + NADPH + H+ + O2
tozasertib N-oxide + NADP+ + H2O
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tyramine + NADPH + H+ + O2
4-[(2E)-2-(hydroxyimino)ethyl]phenol + NADP+ + H2O
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sulindac sulfide + NADPH + H+ + O2
sulindac + NADP+ + H2O
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sulindac sulfide + NADPH + H+ + O2
sulindac + NADP+ + H2O
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the enzyme does not display saturability at concentrations through 1 mM of sulindac sulfide
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?
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N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
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?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
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?
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NADPH
dependent on
NADPH
required for activity
NADPH
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required
NADPH
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required for activity
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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
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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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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
0.336
Ethionamide
isozyme FMO3, at pH 9.5 and 37°C
0.0426 - 0.056
Benzydamine
0.0285 - 0.035
Methimazole
0.013 - 0.0548
N,N,N-trimethylamine
0.022 - 0.0693
sulindac sulfide
0.0426
Benzydamine
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in in 0.1 M tricine buffer, pH 7.4, at 37°C
0.045
Benzydamine
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truncated recombinant enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.056
Benzydamine
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wild type enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.0285
Methimazole
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mutant enzyme, at pH and 37°C
0.03
Methimazole
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native enzyme, at pH and 37°C
0.033
Methimazole
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wild type enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.035
Methimazole
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truncated recombinant enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.013 - 0.0548
N,N,N-trimethylamine
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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
0.028
N,N,N-trimethylamine
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recombinant isoform FMO3, at pH 7.4 and 22°C
0.022
sulindac sulfide
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truncated recombinant enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.025
sulindac sulfide
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wild type enzyme, in 50 mM potassium phosphate buffer (pH 7.4), at 37°C
0.0693
sulindac sulfide
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in in 0.1 M tricine buffer, pH 9.0, at 37°C
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0.973
Ethionamide
isozyme FMO3, at pH 9.5 and 37°C
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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
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7.4 - 8.4
the activity is approximately twice as high at pH 8.4 as at pH 7.4
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UniProt
brenda
isozyme FMO3
UniProt
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FMO3 is the major form of flavin-containing monooxygenase expressed in adult human liver
brenda
FMO3 is the major hepatic isozyme in adults
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adult liver
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FMO3 is quantitatively a major human liver monooxygenase
brenda
additional information
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FMO3 is not expressed in HepG2 cells
brenda
additional information
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no activity in fetal human liver, intestine, and kidney
brenda
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malfunction
trimethylaminuria (fish-odor syndrome) is associated with defective hepatic N-oxidation of dietary-derived trimethylamine catalyzed by flavin-containing monooxygenase
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
metabolism
isoform FMO3 in human liver may contribute to the toxicity and/or affect efficacy of ethionamide administration
metabolism
the flavin monooxygenase FMO3 contributes to metabolism of anti-tumour triazoloacridinone, C-1305 (5-dimethylaminopropylamino-8-hydroxytriazoloacridinone), in liver microsomes and Hep-G2 cells
malfunction
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FMO3 deficiency results in trimethylaminuria or the fish-like odour syndrome
malfunction
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mutations of the flavin-containing monooxygenase gene FMO3 cause trimethylaminuria
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FMO3_HUMAN
532
1
60033
Swiss-Prot
other Location (Reliability: 3 )
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56000
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x * 56000, SDS-PAGE
60000
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x * 60000, SDS-PAGE
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?
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x * 60000, SDS-PAGE
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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
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E158K
the mutant shows reduced FMO3 activity
E24D
the mutation impacts the structure of the Rossmann fold involved in FAD binding and does not alter FMO3 catalytic activity
E308G
the mutant shows reduced FMO3 activity
K416N
the mutation has minimal impact on either hydrophilicity or protein structure
N61K
the mutation disrupts the secondary structure of a conserved membrane interaction domain and does not alter FMO3 catalytic activity
V257M
the mutant shows reduced FMO3 activity
E158K
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the mutation is associated with trimethylaminuria
E305X
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the mutation is associated with trimethylaminuria
E308G
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the mutation is associated with trimethylaminuria
M66I
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the mutation is associated with trimethylaminuria
N245N
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the mutation is associated with trimethylaminuria
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)
V257M
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the mutation is associated with trimethylaminuria
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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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expressed in Sf9 insect cells
expressed in Escherichia coli
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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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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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Adali, O.; Carver, G.C.; Philpot, R.M.
The effect of arginine-428 mutation on modulation of activity of human liver flavin monooxygenase 3 (FMO3) by imipramine and chlorpromazine
Exp. Toxicol. Pathol.
51
271-276
1999
Homo sapiens
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Klick, D.E.; Shadley, J.D.; Hines, R.N.
Differential regulation of human hepatic flavin containing monooxygenase 3 (FMO3) by CCAAT/enhancer-binding protein beta (C/EBPbeta) liver inhibitory and liver activating proteins
Biochem. Pharmacol.
76
268-278
2008
Homo sapiens
brenda
Lickteig, A.J.; Riley, R.; Melton, R.J.; Reitz, B.A.; Fischer, H.D.; Stevens, J.C.
Expression and characterization of functional dog flavin-containing monooxygenase 3
Drug Metab. Dispos.
37
1987-1990
2009
Canis lupus familiaris, Homo sapiens
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Henderson, M.C.; Siddens, L.K.; Morre, J.T.; Krueger, S.K.; Williams, D.E.
Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes
Toxicol. Appl. Pharmacol.
233
420-427
2008
Homo sapiens (P31513), Mus musculus (P97501)
brenda
Lang, D.H.; Yeung, C.K.; Peter, R.M.; Ibarra, C.; Gasser, R.; Itagaki, K.; Philpot, R.M.; Rettie, A.E.
Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3
Biochem. Pharmacol.
56
1005-1012
1998
Homo sapiens
brenda
Catucci, G.; Gilardi, G.; Jeuken, L.; Sadeghi, S.
In vitro drug metabolism by C-terminally truncated human flavin-containing monooxygenase 3
Biochem. Pharmacol.
83
551-558
2012
Homo sapiens
brenda
Haining, R.; Hunter, A.; Sadeque, A.; Philpot, R.; Rettie, A.
Baculovirus-mediated expression and purification of human FMO3: Catalytic, immunochemical, and structural characterization
Drug Metab. Dispos.
25
790-797
1997
Homo sapiens
brenda
Dolphin, C.; Riley, J.; Smith L, R.; Shephard, E.; Phillips, I.
Structural organization of the human flavin-containing monooxygenase 3 gene (FMO3), the favored candidate for fish-odor syndrome, determined directly from genomic DNA
Genomics
46
260-267
1997
Homo sapiens (P31513)
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Treacy, E.; Akerman, B.; Chow, L.; Youil, R.; Bibeau, C.; Lin, J.; Bruce, A.; Knight, M.; Danks, D.; Cashman, J.; Forrest, S.
Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication
Hum. Mol. Genet.
7
839-845
1998
Homo sapiens
brenda
Koukouritaki, S.; Poch, M.; Cabacungan, E.; McCarver, D.; Hines, R.
Discovery of novel flavin-containing monooxygenase 3 (FMO3) single nucleotide polymorphisms and functional analysis of upstream haplotype variants
Mol. Pharmacol.
68
383-392
2005
Homo sapiens (P31513)
brenda
Mitchell, S.; Smith, R.
A physiological role for flavin-containing monooxygenase (FMO3) in humans
Xenobiotica
40
301-305
2010
Homo sapiens
brenda
Fedejko-Kap, B.; Niemira, M.; Radominska-Pandya, A.; Mazerska, Z.
Flavin monooxygenases, FMO1 and FMO3, not cytochrome P450 isoenzymes, contribute to metabolism of anti-tumour triazoloacridinone, C-1305, in liver microsomes and HepG2 cells
Xenobiotica
41
1044-1055
2011
Rattus norvegicus, Homo sapiens (P31513)
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