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Information on EC 1.14.13.148 - trimethylamine monooxygenase and Organism(s) Homo sapiens and UniProt Accession P31513

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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].
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Homo sapiens
UNIPROT: P31513
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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
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
EC 1.14.13.8
assigned to
flavin-containing monooxygenase
-
flavin-containing monooxygenase 3
-
EC 1.14.13.8
-
assigned to
flavin containing monooxygenase 3
-
-
flavin monooxygenase 3
-
-
flavin-containing monooxygenase
-
-
flavin-containing monooxygenase 3
-
-
TMA N-oxygenase
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
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].
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
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
-
-
-
?
ethionamide + NADPH + H+ + O2
ethionamide S-oxide + 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
-
-
-
?
10-[(N,N-dimethylaminopentyl)]-2-(trifluoromethylphenothiazine) + NADPH + H+ + O2
?
show the reaction diagram
-
functional substrate
-
-
?
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
-
-
-
-
?
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
4-[(2E)-2-(hydroxyimino)ethyl]phenol + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
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
-
-
-
?
N,N,N-trimethylamine + NADPH + H+ + O2
N,N,N-trimethylamine N-oxide + NADP+ + H2O
show the reaction diagram
-
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADPH
NADPH
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
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
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
0.336
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
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.973
Ethionamide
isozyme FMO3, at pH 9.5 and 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.049
-
crude enzyme from membranes, using methyl 4-tolyl sulfide as substrate, in 25 mM potassium diphosphate (pH 8.5), at 37°C
0.201
-
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
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
trimethylaminuria (fish-odor syndrome) is associated with defective hepatic N-oxidation of dietary-derived trimethylamine catalyzed by flavin-containing monooxygenase
metabolism
malfunction
physiological function
-
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
FMO3_HUMAN
532
1
60033
Swiss-Prot
other Location (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
56000
-
x * 56000, SDS-PAGE
60000
-
x * 60000, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
-
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
-
the mutation is associated with trimethylaminuria
E305X
-
the mutation is associated with trimethylaminuria
E308G
-
the mutation is associated with trimethylaminuria
M66I
-
the mutation is associated with trimethylaminuria
N245N
-
the mutation is associated with trimethylaminuria
P153L
-
the mutation is associated with trimethylaminuria
P153L/E305X
-
the mutation is associated with trimethylaminuria
S310S
-
the mutation is associated with trimethylaminuria
T428R
-
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
-
the mutation is associated with trimethylaminuria
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
cholate solubilization and sequential column chromatography on octyl-Sepharose, DEAE-Sepharose, and hydroxyapatite
-
DEAE ion exchange column chromatography and Ni affinity column chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Sf9 insect cells
expressed in Escherichia coli
-
expressed in Trichoplusia ni cells and in Escherichia coli strain XL-1 Blue
-
expressed in Trichoplusia ni cells using a baculovirus expression vector system
-
wild type and truncated enzymes are expressed in Escherichia coli JM109 cells
-
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
-
no changes in relative FMO3 mRNA levels are observed with 50 nM trichostatin A
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team
Mitchell, S.; Smith, R.
A physiological role for flavin-containing monooxygenase (FMO3) in humans
Xenobiotica
40
301-305
2010
Homo sapiens
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team