ID   FMO4_HUMAN              Reviewed;         558 AA.
AC   P31512; Q53XR0;
DT   01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   27-MAR-2024, entry version 196.
DE   RecName: Full=Dimethylaniline monooxygenase [N-oxide-forming] 4;
DE            EC=1.14.13.8;
DE   AltName: Full=Dimethylaniline oxidase 4;
DE   AltName: Full=Hepatic flavin-containing monooxygenase 4;
DE            Short=FMO 4;
GN   Name=FMO4; Synonyms=FMO2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   PubMed=1417778; DOI=10.1042/bj2870261;
RA   Dolphin C.T., Shephard E.A., Povey S., Smith R.L., Phillips I.R.;
RT   "Cloning, primary sequence and chromosomal localization of human FMO2, a
RT   new member of the flavin-containing mono-oxygenase family.";
RL   Biochem. J. 287:261-267(1992).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ALA-323; SER-372; LEU-536
RP   AND ARG-544.
RG   NIEHS SNPs program;
RL   Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Skin;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [8]
RP   VARIANTS THR-37; ALA-323 AND GLN-339.
RX   PubMed=12527699; DOI=10.1124/dmd.31.2.187;
RA   Furnes B., Feng J., Sommer S.S., Schlenk D.;
RT   "Identification of novel variants of the flavin-containing monooxygenase
RT   gene family in African Americans.";
RL   Drug Metab. Dispos. 31:187-193(2003).
RN   [9]
RP   VARIANT HIS-28.
RX   PubMed=28940097; DOI=10.1007/s00439-017-1843-2;
RA   Anazi S., Maddirevula S., Salpietro V., Asi Y.T., Alsahli S., Alhashem A.,
RA   Shamseldin H.E., AlZahrani F., Patel N., Ibrahim N., Abdulwahab F.M.,
RA   Hashem M., Alhashmi N., Al Murshedi F., Al Kindy A., Alshaer A.,
RA   Rumayyan A., Al Tala S., Kurdi W., Alsaman A., Alasmari A., Banu S.,
RA   Sultan T., Saleh M.M., Alkuraya H., Salih M.A., Aldhalaan H., Ben-Omran T.,
RA   Al Musafri F., Ali R., Suleiman J., Tabarki B., El-Hattab A.W., Bupp C.,
RA   Alfadhel M., Al Tassan N., Monies D., Arold S.T., Abouelhoda M.,
RA   Lashley T., Houlden H., Faqeih E., Alkuraya F.S.;
RT   "Expanding the genetic heterogeneity of intellectual disability.";
RL   Hum. Genet. 136:1419-1429(2017).
RN   [10]
RP   ERRATUM OF PUBMED:28940097.
RX   PubMed=29288388; DOI=10.1007/s00439-017-1859-7;
RA   Anazi S., Maddirevula S., Salpietro V., Asi Y.T., Alsahli S., Alhashem A.,
RA   Shamseldin H.E., AlZahrani F., Patel N., Ibrahim N., Abdulwahab F.M.,
RA   Hashem M., Alhashmi N., Al Murshedi F., Al Kindy A., Alshaer A.,
RA   Rumayyan A., Al Tala S., Kurdi W., Alsaman A., Alasmari A., Banu S.,
RA   Sultan T., Saleh M.M., Alkuraya H., Salih M.A., Aldhalaan H., Ben-Omran T.,
RA   Al Musafri F., Ali R., Suleiman J., Tabarki B., El-Hattab A.W., Bupp C.,
RA   Alfadhel M., Al Tassan N., Monies D., Arold S.T., Abouelhoda M.,
RA   Lashley T., Houlden H., Faqeih E., Alkuraya F.S.;
RT   "Correction to: Expanding the genetic heterogeneity of intellectual
RT   disability.";
RL   Hum. Genet. 137:105-109(2018).
CC   -!- FUNCTION: This protein is involved in the oxidative metabolism of a
CC       variety of xenobiotics such as drugs and pesticides.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H(+) + N,N-dimethylaniline + NADPH + O2 = H2O + N,N-
CC         dimethylaniline N-oxide + NADP(+); Xref=Rhea:RHEA:24468,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:16269, ChEBI:CHEBI:17735, ChEBI:CHEBI:57783,
CC         ChEBI:CHEBI:58349; EC=1.14.13.8;
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC   -!- INTERACTION:
CC       P31512; Q6NTF9-3: RHBDD2; NbExp=3; IntAct=EBI-17589491, EBI-17589229;
CC   -!- SUBCELLULAR LOCATION: Microsome membrane
CC       {ECO:0000250|UniProtKB:Q8K4B7}; Single-pass membrane protein
CC       {ECO:0000255}. Endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:Q8K4B7}; Single-pass membrane protein
CC       {ECO:0000255}.
CC   -!- TISSUE SPECIFICITY: Liver.
CC   -!- SIMILARITY: Belongs to the FMO family. {ECO:0000305}.
CC   -!- CAUTION: Was originally termed FMO2. {ECO:0000305|PubMed:1417778}.
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/fmo4/";
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DR   EMBL; Z11737; CAA77797.1; -; mRNA.
DR   EMBL; AY882422; AAW56938.1; -; Genomic_DNA.
DR   EMBL; BT007444; AAP36112.1; -; mRNA.
DR   EMBL; AL031274; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471067; EAW90896.1; -; Genomic_DNA.
DR   EMBL; BC002780; AAH02780.1; -; mRNA.
DR   CCDS; CCDS1295.1; -.
DR   PIR; S29125; S29125.
DR   RefSeq; NP_002013.1; NM_002022.2.
DR   AlphaFoldDB; P31512; -.
DR   SMR; P31512; -.
DR   BioGRID; 108616; 2.
DR   IntAct; P31512; 1.
DR   STRING; 9606.ENSP00000356723; -.
DR   ChEMBL; CHEMBL3542432; -.
DR   iPTMnet; P31512; -.
DR   PhosphoSitePlus; P31512; -.
DR   BioMuta; FMO4; -.
DR   DMDM; 399506; -.
DR   jPOST; P31512; -.
DR   MassIVE; P31512; -.
DR   PaxDb; 9606-ENSP00000356723; -.
DR   PeptideAtlas; P31512; -.
DR   ProteomicsDB; 54792; -.
DR   Antibodypedia; 34378; 121 antibodies from 22 providers.
DR   DNASU; 2329; -.
DR   Ensembl; ENST00000367749.4; ENSP00000356723.3; ENSG00000076258.10.
DR   GeneID; 2329; -.
DR   KEGG; hsa:2329; -.
DR   MANE-Select; ENST00000367749.4; ENSP00000356723.3; NM_002022.3; NP_002013.1.
DR   UCSC; uc001gho.4; human.
DR   AGR; HGNC:3772; -.
DR   CTD; 2329; -.
DR   DisGeNET; 2329; -.
DR   GeneCards; FMO4; -.
DR   HGNC; HGNC:3772; FMO4.
DR   HPA; ENSG00000076258; Group enriched (kidney, liver).
DR   MIM; 136131; gene.
DR   neXtProt; NX_P31512; -.
DR   OpenTargets; ENSG00000076258; -.
DR   PharmGKB; PA28188; -.
DR   VEuPathDB; HostDB:ENSG00000076258; -.
DR   eggNOG; KOG1399; Eukaryota.
DR   GeneTree; ENSGT00940000160256; -.
DR   HOGENOM; CLU_006909_8_2_1; -.
DR   InParanoid; P31512; -.
DR   OMA; HYLKVWG; -.
DR   OrthoDB; 2079054at2759; -.
DR   PhylomeDB; P31512; -.
DR   TreeFam; TF105285; -.
DR   BRENDA; 1.14.13.8; 2681.
DR   PathwayCommons; P31512; -.
DR   SignaLink; P31512; -.
DR   BioGRID-ORCS; 2329; 9 hits in 1148 CRISPR screens.
DR   ChiTaRS; FMO4; human.
DR   GeneWiki; FMO4; -.
DR   GenomeRNAi; 2329; -.
DR   Pharos; P31512; Tbio.
DR   PRO; PR:P31512; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; P31512; Protein.
DR   Bgee; ENSG00000076258; Expressed in nephron tubule and 134 other cell types or tissues.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR   GO; GO:0047822; F:hypotaurine dehydrogenase activity; IEA:UniProtKB-EC.
DR   GO; GO:0004499; F:N,N-dimethylaniline monooxygenase activity; IBA:GO_Central.
DR   GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR   GO; GO:0097009; P:energy homeostasis; IEA:Ensembl.
DR   GO; GO:0046322; P:negative regulation of fatty acid oxidation; IEA:Ensembl.
DR   GO; GO:0042178; P:xenobiotic catabolic process; IEA:Ensembl.
DR   Gene3D; 3.50.50.60; FAD/NAD(P)-binding domain; 1.
DR   InterPro; IPR036188; FAD/NAD-bd_sf.
DR   InterPro; IPR000960; Flavin_mOase.
DR   InterPro; IPR020946; Flavin_mOase-like.
DR   InterPro; IPR002256; Flavin_mOase_4.
DR   PANTHER; PTHR23023; DIMETHYLANILINE MONOOXYGENASE; 1.
DR   PANTHER; PTHR23023:SF74; DIMETHYLANILINE MONOOXYGENASE [N-OXIDE-FORMING] 4; 1.
DR   Pfam; PF00743; FMO-like; 1.
DR   PIRSF; PIRSF000332; FMO; 1.
DR   PRINTS; PR00370; FMOXYGENASE.
DR   PRINTS; PR01124; FMOXYGENASE4.
DR   SUPFAM; SSF51905; FAD/NAD(P)-binding domain; 2.
DR   Genevisible; P31512; HS.
PE   1: Evidence at protein level;
KW   Endoplasmic reticulum; FAD; Flavoprotein; Membrane; Microsome;
KW   Monooxygenase; NADP; Oxidoreductase; Reference proteome; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..558
FT                   /note="Dimethylaniline monooxygenase [N-oxide-forming] 4"
FT                   /id="PRO_0000147660"
FT   TRANSMEM        517..537
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         9..13
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT   BINDING         32
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT   BINDING         40..41
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT   BINDING         60..61
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT   BINDING         195..198
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:Q9HFE4"
FT   VARIANT         28
FT                   /note="P -> H (found in a patient with intellectual
FT                   disability; uncertain significance; dbSNP:rs866374389)"
FT                   /evidence="ECO:0000269|PubMed:28940097"
FT                   /id="VAR_084652"
FT   VARIANT         37
FT                   /note="I -> T (in dbSNP:rs72549338)"
FT                   /evidence="ECO:0000269|PubMed:12527699"
FT                   /id="VAR_015367"
FT   VARIANT         308
FT                   /note="T -> S (in dbSNP:rs3737925)"
FT                   /id="VAR_049090"
FT   VARIANT         323
FT                   /note="V -> A (in dbSNP:rs1042767)"
FT                   /evidence="ECO:0000269|PubMed:12527699, ECO:0000269|Ref.2"
FT                   /id="VAR_015368"
FT   VARIANT         339
FT                   /note="E -> Q (in dbSNP:rs61342270)"
FT                   /evidence="ECO:0000269|PubMed:12527699"
FT                   /id="VAR_015369"
FT   VARIANT         372
FT                   /note="G -> S (in dbSNP:rs45599742)"
FT                   /evidence="ECO:0000269|Ref.2"
FT                   /id="VAR_022305"
FT   VARIANT         536
FT                   /note="F -> L (in dbSNP:rs45487792)"
FT                   /evidence="ECO:0000269|Ref.2"
FT                   /id="VAR_022306"
FT   VARIANT         544
FT                   /note="L -> R (in dbSNP:rs45528740)"
FT                   /evidence="ECO:0000269|Ref.2"
FT                   /id="VAR_022307"
SQ   SEQUENCE   558 AA;  63343 MW;  6981AE9180C07802 CRC64;
     MAKKVAVIGA GVSGLSSIKC CVDEDLEPTC FERSDDIGGL WKFTESSKDG MTRVYKSLVT
     NVCKEMSCYS DFPFHEDYPN FMNHEKFWDY LQEFAEHFDL LKYIQFKTTV CSITKRPDFS
     ETGQWDVVTE TEGKQNRAVF DAVMVCTGHF LNPHLPLEAF PGIHKFKGQI LHSQEYKIPE
     GFQGKRVLVI GLGNTGGDIA VELSRTAAQV LLSTRTGTWV LGRSSDWGYP YNMMVTRRCC
     SFIAQVLPSR FLNWIQERKL NKRFNHEDYG LSITKGKKAK FIVNDELPNC ILCGAITMKT
     SVIEFTETSA VFEDGTVEEN IDVVIFTTGY TFSFPFFEEP LKSLCTKKIF LYKQVFPLNL
     ERATLAIIGL IGLKGSILSG TELQARWVTR VFKGLCKIPP SQKLMMEATE KEQLIKRGVF
     KDTSKDKFDY IAYMDDIAAC IGTKPSIPLL FLKDPRLAWE VFFGPCTPYQ YRLMGPGKWD
     GARNAILTQW DRTLKPLKTR IVPDSSKPAS MSHYLKAWGA PVLLASLLLI CKSSLFLKLV
     RDKLQDRMSP YLVSLWRG
//