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Protein

Dimethylaniline monooxygenase [N-oxide-forming] 3

Gene

FMO3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an important role in the metabolism of trimethylamine (TMA), via the production of TMA N-oxide (TMAO). Is also able to perform S-oxidation when acting on sulfide compounds (PubMed:9224773).By similarity1 Publication

Catalytic activityi

N,N-dimethylaniline + NADPH + O2 = N,N-dimethylaniline N-oxide + NADP+ + H2O.1 Publication
N,N,N-trimethylamine + NADPH + O2 = N,N,N-trimethylamine N-oxide + NADP+ + H2O.1 Publication

Cofactori

Kineticsi

  1. KM=21 µM for trimethylamine (at pH 8.5)2 Publications
  2. KM=31 µM for trimethylamine (at pH 7.4 and 37 degrees Celsius)2 Publications
  3. KM=43 µM for benzydamine (at pH 7.4 and 37 degrees Celsius)2 Publications
  4. KM=55.7 µM for ethylenethiourea (at pH 8.5)2 Publications
  5. KM=71.8 µM for methimazole (at pH 8.5)2 Publications
  6. KM=150.1 µM for sulindac (at pH 8.5)2 Publications
  7. KM=248 µM for methyl p-tolyl sulfide (at pH 7.4 and 37 degrees Celsius)2 Publications

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi9 – 14FADSequence analysis6
    Nucleotide bindingi191 – 196NADPSequence analysis6

    GO - Molecular functioni

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Monooxygenase, Oxidoreductase

    Keywords - Ligandi

    FAD, Flavoprotein, NADP

    Enzyme and pathway databases

    BioCyciMetaCyc:HS00223-MONOMER.
    ZFISH:HS00223-MONOMER.
    BRENDAi1.14.13.148. 2681.
    1.14.13.8. 2681.
    ReactomeiR-HSA-217271. FMO oxidises nucleophiles.
    SABIO-RKP31513.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dimethylaniline monooxygenase [N-oxide-forming] 3 (EC:1.14.13.8)
    Alternative name(s):
    Dimethylaniline oxidase 3
    FMO II
    FMO form 2
    Hepatic flavin-containing monooxygenase 3
    Short name:
    FMO 3
    Trimethylamine monooxygenase (EC:1.14.13.148)
    Gene namesi
    Name:FMO3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 1

    Organism-specific databases

    HGNCiHGNC:3771. FMO3.

    Subcellular locationi

    GO - Cellular componenti

    Complete GO annotation...

    Keywords - Cellular componenti

    Endoplasmic reticulum, Membrane, Microsome

    Pathology & Biotechi

    Involvement in diseasei

    Trimethylaminuria (TMAU)5 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionInborn error of metabolism associated with an offensive body odor and caused by deficiency of FMO-mediated N-oxidation of amino-trimethylamine (TMA) derived from foodstuffs. Affected individuals excrete relatively large amounts of TMA in their urine, sweat, and breath, and exhibit a fishy body odor characteristic of the malodorous free amine.
    See also OMIM:602079
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_03730632E → K in TMAU. 1 PublicationCorresponds to variant rs72549320dbSNPEnsembl.1
    Natural variantiVAR_00814652A → T in TMAU. 1 PublicationCorresponds to variant rs72549321dbSNPEnsembl.1
    Natural variantiVAR_03730761N → S in TMAU; more than 90% reduction in catalytic efficiency toward trimethylamine, benzydamine and methyl p-tolyl sulfide. 2 PublicationsCorresponds to variant rs72549322dbSNPEnsembl.1
    Natural variantiVAR_00242366M → I in TMAU; loss of activity; affects FAD binding. 3 PublicationsCorresponds to variant rs72549323dbSNPEnsembl.1
    Natural variantiVAR_002424153P → L in TMAU; 90% reduction in catalytic efficiency toward trimethylamine and benzydamine; 34% reduction in catalytic efficiency toward methyl p-tolyl sulfide; nearly no effect on affinity for these substrates. 3 PublicationsCorresponds to variant rs72549326dbSNPEnsembl.1
    Natural variantiVAR_008147387R → L in TMAU. 1 PublicationCorresponds to variant rs72549331dbSNPEnsembl.1
    Natural variantiVAR_037308434M → I in TMAU; profoundly alters enzyme function. 1 PublicationCorresponds to variant rs72549332dbSNPEnsembl.1
    Natural variantiVAR_008145492R → W in TMAU; loss of activity; affects FAD binding. 3 PublicationsCorresponds to variant rs72549334dbSNPEnsembl.1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi2328.
    MalaCardsiFMO3.
    MIMi602079. phenotype.
    OpenTargetsiENSG00000007933.
    Orphaneti35056. Trimethylaminuria.
    PharmGKBiPA166.

    Chemistry databases

    ChEMBLiCHEMBL3430864.
    DrugBankiDB00918. Almotriptan.
    DB00501. Cimetidine.
    DB00363. Clozapine.
    DB00250. Dapsone.
    DB01254. Dasatinib.
    DB00334. Olanzapine.
    DB00675. Tamoxifen.
    DB05294. Vandetanib.
    DB00582. Voriconazole.

    Polymorphism and mutation databases

    BioMutaiFMO3.
    DMDMi6166183.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemoved1 Publication
    ChainiPRO_00001476542 – 532Dimethylaniline monooxygenase [N-oxide-forming] 3Add BLAST531

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei401PhosphoserineBy similarity1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    PaxDbiP31513.
    PeptideAtlasiP31513.
    PRIDEiP31513.

    PTM databases

    iPTMnetiP31513.
    PhosphoSitePlusiP31513.

    Expressioni

    Tissue specificityi

    Liver.

    Gene expression databases

    BgeeiENSG00000007933.
    CleanExiHS_FMO3.
    ExpressionAtlasiP31513. baseline and differential.
    GenevisibleiP31513. HS.

    Organism-specific databases

    HPAiHPA008065.
    HPA013750.

    Interactioni

    Protein-protein interaction databases

    IntActiP31513. 1 interactor.
    STRINGi9606.ENSP00000356729.

    Structurei

    3D structure databases

    ProteinModelPortaliP31513.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the FMO family.Curated

    Keywords - Domaini

    Transmembrane

    Phylogenomic databases

    eggNOGiKOG1399. Eukaryota.
    COG2072. LUCA.
    GeneTreeiENSGT00760000119232.
    HOGENOMiHOG000076537.
    HOVERGENiHBG002037.
    InParanoidiP31513.
    KOiK00485.
    OMAiQVIKGTC.
    OrthoDBiEOG091G0465.
    PhylomeDBiP31513.
    TreeFamiTF105285.

    Family and domain databases

    Gene3Di3.50.50.60. 4 hits.
    InterProiIPR012143. DiMe-aniline_mOase.
    IPR023753. FAD/NAD-binding_dom.
    IPR000960. Flavin_mOase.
    IPR020946. Flavin_mOase-like.
    IPR002255. Flavin_mOase_3.
    [Graphical view]
    PfamiPF00743. FMO-like. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000332. FMO. 1 hit.
    PRINTSiPR00370. FMOXYGENASE.
    PR01123. FMOXYGENASE3.
    SUPFAMiSSF51905. SSF51905. 2 hits.

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P31513-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MGKKVAIIGA GVSGLASIRS CLEEGLEPTC FEKSNDIGGL WKFSDHAEEG
    60 70 80 90 100
    RASIYKSVFS NSSKEMMCFP DFPFPDDFPN FMHNSKIQEY IIAFAKEKNL
    110 120 130 140 150
    LKYIQFKTFV SSVNKHPDFA TTGQWDVTTE RDGKKESAVF DAVMVCSGHH
    160 170 180 190 200
    VYPNLPKESF PGLNHFKGKC FHSRDYKEPG VFNGKRVLVV GLGNSGCDIA
    210 220 230 240 250
    TELSRTAEQV MISSRSGSWV MSRVWDNGYP WDMLLVTRFG TFLKNNLPTA
    260 270 280 290 300
    ISDWLYVKQM NARFKHENYG LMPLNGVLRK EPVFNDELPA SILCGIVSVK
    310 320 330 340 350
    PNVKEFTETS AIFEDGTIFE GIDCVIFATG YSFAYPFLDE SIIKSRNNEI
    360 370 380 390 400
    ILFKGVFPPL LEKSTIAVIG FVQSLGAAIP TVDLQSRWAA QVIKGTCTLP
    410 420 430 440 450
    SMEDMMNDIN EKMEKKRKWF GKSETIQTDY IVYMDELSSF IGAKPNIPWL
    460 470 480 490 500
    FLTDPKLAME VYFGPCSPYQ FRLVGPGQWP GARNAILTQW DRSLKPMQTR
    510 520 530
    VVGRLQKPCF FFHWLKLFAI PILLIAVFLV LT
    Length:532
    Mass (Da):60,033
    Last modified:January 23, 2007 - v5
    Checksum:i729E41D53EFC4110
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti298S → T in AAA86284 (PubMed:1542660).Curated1
    Sequence conflicti369I → L in AAA86284 (PubMed:1542660).Curated1
    Sequence conflicti400 – 405PSMEDM → GPFYGKTL in AAA86284 (PubMed:1542660).Curated6
    Sequence conflicti410N → I in AAA86284 (PubMed:1542660).Curated1
    Sequence conflicti418 – 419KW → ANG in AAA86284 (PubMed:1542660).Curated2
    Sequence conflicti444 – 445KP → T in AAA86284 (PubMed:1542660).Curated2
    Sequence conflicti449W → M in AAA86284 (PubMed:1542660).Curated1
    Sequence conflicti454D → G in AAA86284 (PubMed:1542660).Curated1
    Sequence conflicti461 – 462VY → L in AAA86284 (PubMed:1542660).Curated2
    Sequence conflicti478Q → S in AAA86284 (PubMed:1542660).Curated1
    Sequence conflicti486I → M in CAA87632 (PubMed:8654418).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_04270524E → D Modest increase in catalytic efficiency toward trimethylamine, methimazole, ethylenethiourea and sulindac. 1 Publication1
    Natural variantiVAR_03730632E → K in TMAU. 1 PublicationCorresponds to variant rs72549320dbSNPEnsembl.1
    Natural variantiVAR_00814652A → T in TMAU. 1 PublicationCorresponds to variant rs72549321dbSNPEnsembl.1
    Natural variantiVAR_04270661N → K Loss of activity. 1 Publication1
    Natural variantiVAR_03730761N → S in TMAU; more than 90% reduction in catalytic efficiency toward trimethylamine, benzydamine and methyl p-tolyl sulfide. 2 PublicationsCorresponds to variant rs72549322dbSNPEnsembl.1
    Natural variantiVAR_00242366M → I in TMAU; loss of activity; affects FAD binding. 3 PublicationsCorresponds to variant rs72549323dbSNPEnsembl.1
    Natural variantiVAR_015364132D → H.2 PublicationsCorresponds to variant rs12072582dbSNPEnsembl.1
    Natural variantiVAR_002424153P → L in TMAU; 90% reduction in catalytic efficiency toward trimethylamine and benzydamine; 34% reduction in catalytic efficiency toward methyl p-tolyl sulfide; nearly no effect on affinity for these substrates. 3 PublicationsCorresponds to variant rs72549326dbSNPEnsembl.1
    Natural variantiVAR_002425158E → K 35%, 45% and 71% increase in catalytic efficiency toward trimethylamine, benzydamine and methyl p-tolyl sulfide, respectively. 6 PublicationsCorresponds to variant rs2266782dbSNPEnsembl.1
    Natural variantiVAR_018345198D → E.1 PublicationCorresponds to variant rs529940450dbSNPEnsembl.1
    Natural variantiVAR_018346205R → C.2 PublicationsCorresponds to variant rs28363549dbSNPEnsembl.1
    Natural variantiVAR_002426257V → M 65% increase in catalytic efficiency toward trimethylamine and 60% reduction toward benzydamine and methyl p-tolyl sulfide. 6 PublicationsCorresponds to variant rs1736557dbSNPEnsembl.1
    Natural variantiVAR_014845277V → A.1 PublicationCorresponds to variant rs2066530dbSNPEnsembl.1
    Natural variantiVAR_002427308E → G 16% reduction in catalytic efficiency toward trimethylamine and 40% increase toward benzydamine and methyl p-tolyl sulfide. 5 PublicationsCorresponds to variant rs2266780dbSNPEnsembl.1
    Natural variantiVAR_015365360L → P.2 PublicationsCorresponds to variant rs28363581dbSNPEnsembl.1
    Natural variantiVAR_014846362E → Q.2 PublicationsCorresponds to variant rs2066532dbSNPEnsembl.1
    Natural variantiVAR_008147387R → L in TMAU. 1 PublicationCorresponds to variant rs72549331dbSNPEnsembl.1
    Natural variantiVAR_042707416K → N 2-fold decrease in affinity for trimethylamine; 3-fold decrease in catalytic efficiency toward methimazole; 3-fold increase in catalytic efficiency toward sulindac; 30% increase in catalytic efficiency toward ethylenethiourea. 1 PublicationCorresponds to variant rs774785217dbSNPEnsembl.1
    Natural variantiVAR_037308434M → I in TMAU; profoundly alters enzyme function. 1 PublicationCorresponds to variant rs72549332dbSNPEnsembl.1
    Natural variantiVAR_008145492R → W in TMAU; loss of activity; affects FAD binding. 3 PublicationsCorresponds to variant rs72549334dbSNPEnsembl.1
    Natural variantiVAR_015366503G → R.1 PublicationCorresponds to variant rs72549335dbSNPEnsembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M83772 mRNA. Translation: AAA86284.1.
    Z47552 mRNA. Translation: CAA87632.1.
    U39967
    , U39961, U39962, U39963, U39964, U39965, U39966 Genomic DNA. Translation: AAC51932.1.
    AY895830 Genomic DNA. Translation: AAW65372.1.
    AK313197 mRNA. Translation: BAG36013.1.
    AL021026 Genomic DNA. Translation: CAA15908.1.
    CH471067 Genomic DNA. Translation: EAW90887.1.
    BC032016 mRNA. Translation: AAH32016.1.
    CCDSiCCDS1292.1.
    PIRiA38228.
    S62367. S51130.
    RefSeqiNP_001002294.1. NM_001002294.2.
    NP_001306102.1. NM_001319173.1.
    NP_001306103.1. NM_001319174.1.
    NP_008825.4. NM_006894.5.
    UniGeneiHs.445350.

    Genome annotation databases

    EnsembliENST00000367755; ENSP00000356729; ENSG00000007933.
    GeneIDi2328.
    KEGGihsa:2328.
    UCSCiuc001ghi.3. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Web resourcesi

    NIEHS-SNPs
    Protein Spotlight

    A case for discomfort - Issue 149 of June 2013

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M83772 mRNA. Translation: AAA86284.1.
    Z47552 mRNA. Translation: CAA87632.1.
    U39967
    , U39961, U39962, U39963, U39964, U39965, U39966 Genomic DNA. Translation: AAC51932.1.
    AY895830 Genomic DNA. Translation: AAW65372.1.
    AK313197 mRNA. Translation: BAG36013.1.
    AL021026 Genomic DNA. Translation: CAA15908.1.
    CH471067 Genomic DNA. Translation: EAW90887.1.
    BC032016 mRNA. Translation: AAH32016.1.
    CCDSiCCDS1292.1.
    PIRiA38228.
    S62367. S51130.
    RefSeqiNP_001002294.1. NM_001002294.2.
    NP_001306102.1. NM_001319173.1.
    NP_001306103.1. NM_001319174.1.
    NP_008825.4. NM_006894.5.
    UniGeneiHs.445350.

    3D structure databases

    ProteinModelPortaliP31513.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    IntActiP31513. 1 interactor.
    STRINGi9606.ENSP00000356729.

    Chemistry databases

    ChEMBLiCHEMBL3430864.
    DrugBankiDB00918. Almotriptan.
    DB00501. Cimetidine.
    DB00363. Clozapine.
    DB00250. Dapsone.
    DB01254. Dasatinib.
    DB00334. Olanzapine.
    DB00675. Tamoxifen.
    DB05294. Vandetanib.
    DB00582. Voriconazole.

    PTM databases

    iPTMnetiP31513.
    PhosphoSitePlusiP31513.

    Polymorphism and mutation databases

    BioMutaiFMO3.
    DMDMi6166183.

    Proteomic databases

    PaxDbiP31513.
    PeptideAtlasiP31513.
    PRIDEiP31513.

    Protocols and materials databases

    DNASUi2328.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000367755; ENSP00000356729; ENSG00000007933.
    GeneIDi2328.
    KEGGihsa:2328.
    UCSCiuc001ghi.3. human.

    Organism-specific databases

    CTDi2328.
    DisGeNETi2328.
    GeneCardsiFMO3.
    GeneReviewsiFMO3.
    HGNCiHGNC:3771. FMO3.
    HPAiHPA008065.
    HPA013750.
    MalaCardsiFMO3.
    MIMi136132. gene.
    602079. phenotype.
    neXtProtiNX_P31513.
    OpenTargetsiENSG00000007933.
    Orphaneti35056. Trimethylaminuria.
    PharmGKBiPA166.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG1399. Eukaryota.
    COG2072. LUCA.
    GeneTreeiENSGT00760000119232.
    HOGENOMiHOG000076537.
    HOVERGENiHBG002037.
    InParanoidiP31513.
    KOiK00485.
    OMAiQVIKGTC.
    OrthoDBiEOG091G0465.
    PhylomeDBiP31513.
    TreeFamiTF105285.

    Enzyme and pathway databases

    BioCyciMetaCyc:HS00223-MONOMER.
    ZFISH:HS00223-MONOMER.
    BRENDAi1.14.13.148. 2681.
    1.14.13.8. 2681.
    ReactomeiR-HSA-217271. FMO oxidises nucleophiles.
    SABIO-RKP31513.

    Miscellaneous databases

    GeneWikiiFlavin_containing_monooxygenase_3.
    GenomeRNAii2328.
    PROiP31513.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000007933.
    CleanExiHS_FMO3.
    ExpressionAtlasiP31513. baseline and differential.
    GenevisibleiP31513. HS.

    Family and domain databases

    Gene3Di3.50.50.60. 4 hits.
    InterProiIPR012143. DiMe-aniline_mOase.
    IPR023753. FAD/NAD-binding_dom.
    IPR000960. Flavin_mOase.
    IPR020946. Flavin_mOase-like.
    IPR002255. Flavin_mOase_3.
    [Graphical view]
    PfamiPF00743. FMO-like. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000332. FMO. 1 hit.
    PRINTSiPR00370. FMOXYGENASE.
    PR01123. FMOXYGENASE3.
    SUPFAMiSSF51905. SSF51905. 2 hits.
    ProtoNetiSearch...

    Entry informationi

    Entry nameiFMO3_HUMAN
    AccessioniPrimary (citable) accession number: P31513
    Secondary accession number(s): B2R816, Q14854, Q8N5N5
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 1, 1993
    Last sequence update: January 23, 2007
    Last modified: November 30, 2016
    This is version 173 of the entry and version 5 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 1
      Human chromosome 1: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. Protein Spotlight
      Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
    6. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.