FMO3_HUMAN
ID FMO3_HUMAN Reviewed; 532 AA.
AC P31513; B2R816; Q14854; Q8N5N5;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 5.
DT 03-AUG-2022, entry version 207.
DE RecName: Full=Dimethylaniline monooxygenase [N-oxide-forming] 3;
DE EC=1.14.13.8 {ECO:0000269|PubMed:9536088};
DE EC=1.14.14.73 {ECO:0000269|PubMed:10759686};
DE AltName: Full=Dimethylaniline oxidase 3;
DE AltName: Full=FMO II;
DE AltName: Full=FMO form 2;
DE AltName: Full=Hepatic flavin-containing monooxygenase 3;
DE Short=FMO 3;
DE AltName: Full=Trimethylamine monooxygenase;
DE EC=1.14.13.148;
GN Name=FMO3;
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=1542660; DOI=10.1073/pnas.89.5.1685;
RA Lomri N., Gu Q., Cashman J.R.;
RT "Molecular cloning of the flavin-containing monooxygenase (form II) cDNA
RT from adult human liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:1685-1689(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=8654418; DOI=10.1111/j.1432-1033.1996.00683.x;
RA Dolphin C.T., Cullingford T.E., Shephard E.A., Smith R.L., Phillips I.R.;
RT "Differential developmental and tissue-specific regulation of expression of
RT the genes encoding three members of the flavin-containing monooxygenase
RT family of man, FMO1, FMO3 and FM04.";
RL Eur. J. Biochem. 235:683-689(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9417913; DOI=10.1006/geno.1997.5031;
RA Dolphin C.T., Riley J.H., Smith R.L., Shephard E.A., Phillips I.R.;
RT "Structural organization of the human flavin-containing monooxygenase 3
RT gene (FMO3), the favored candidate for fish-odor syndrome, determined
RT directly from genomic DNA.";
RL Genomics 46:260-267(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-132; LYS-158; CYS-205;
RP MET-257; ALA-277; GLY-308; PRO-360 AND GLN-362.
RG NIEHS SNPs program;
RL Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
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 [7]
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-257.
RC TISSUE=Brain, and Lung;
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 [9]
RP PROTEIN SEQUENCE OF 2-10, FUNCTION, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=9224773;
RA Haining R.L., Hunter A.P., Sadeque A.J., Philpot R.M., Rettie A.E.;
RT "Baculovirus-mediated expression and purification of human FMO3: catalytic,
RT immunochemical, and structural characterization.";
RL Drug Metab. Dispos. 25:790-797(1997).
RN [10]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=9776311; DOI=10.1016/s0006-2952(98)00218-4;
RA Lang D.H., Yeung C.K., Peter R.M., Ibarra C., Gasser R., Itagaki K.,
RA Philpot R.M., Rettie A.E.;
RT "Isoform specificity of trimethylamine N-oxygenation by human flavin-
RT containing monooxygenase (FMO) and P450 enzymes: selective catalysis by
RT FMO3.";
RL Biochem. Pharmacol. 56:1005-1012(1998).
RN [11]
RP CATALYTIC ACTIVITY, VARIANTS TMAU ILE-66 AND LEU-153, AND VARIANTS LYS-158;
RP MET-257 AND GLY-308.
RX PubMed=9536088; DOI=10.1093/hmg/7.5.839;
RA Treacy E.P., Akerman B.R., Chow L.M.L., Youil R., Bibeau C., Lin J.,
RA Bruce A.G., Knight M., Danks D.M., Cashman J.R., Forrest S.M.;
RT "Mutations of the flavin-containing monooxygenase gene (FMO3) cause
RT trimethylaminuria, a defect in detoxication.";
RL Hum. Mol. Genet. 7:839-845(1998).
RN [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=10759686; DOI=10.1046/j.1365-2125.2000.00170.x;
RA Rawden H.C., Kokwaro G.O., Ward S.A., Edwards G.;
RT "Relative contribution of cytochromes P-450 and flavin-containing
RT monooxygenases to the metabolism of albendazole by human liver
RT microsomes.";
RL Br. J. Clin. Pharmacol. 49:313-322(2000).
RN [13]
RP BIOPHYSICOCHEMICAL PROPERTIES, CHARACTERIZATION OF VARIANTS TMAU SER-61;
RP ILE-66; LEU-153 AND TRP-492, AND CHARACTERIZATION OF VARIANTS LYS-158;
RP MET-257 AND GLY-308.
RX PubMed=17531949; DOI=10.1016/j.abb.2007.04.014;
RA Yeung C.K., Adman E.T., Rettie A.E.;
RT "Functional characterization of genetic variants of human FMO3 associated
RT with trimethylaminuria.";
RL Arch. Biochem. Biophys. 464:251-259(2007).
RN [14]
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 [15]
RP FUNCTION.
RX PubMed=29981269; DOI=10.1111/jth.14234;
RA Zhu W., Buffa J.A., Wang Z., Warrier M., Schugar R., Shih D.M., Gupta N.,
RA Gregory J.C., Org E., Fu X., Li L., DiDonato J.A., Lusis A.J., Brown J.M.,
RA Hazen S.L.;
RT "Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal
RT trimethylamine N-oxide-generating pathway, modulates platelet
RT responsiveness and thrombosis risk.";
RL J. Thromb. Haemost. 16:1857-1872(2018).
RN [16]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=30381441; DOI=10.1158/1055-9965.epi-18-0669;
RA Perez-Paramo Y.X., Chen G., Ashmore J.H., Watson C.J.W., Nasrin S.,
RA Adams-Haduch J., Wang R., Gao Y.T., Koh W.P., Yuan J.M., Lazarus P.;
RT "Nicotine-N'-oxidation by flavin monooxygenase enzymes.";
RL Cancer Epidemiol. Biomarkers Prev. 28:311-320(2019).
RN [17]
RP VARIANTS TMAU ILE-66 AND TRP-492.
RX PubMed=10338091;
RX DOI=10.1002/(sici)1098-1004(1999)13:5<376::aid-humu5>3.0.co;2-a;
RA Akerman B.R., Forrest S.M., Chow L.M.L., Youil R., Knight M., Treacy E.P.;
RT "Two novel mutations of the FMO3 gene in a proband with
RT trimethylaminuria.";
RL Hum. Mutat. 13:376-379(1999).
RN [18]
RP VARIANTS TMAU THR-52 AND LEU-387, AND VARIANTS LYS-158 AND GLY-308.
RX PubMed=10479479; DOI=10.1006/mgme.1999.2885;
RA Akerman B.R., Lemass H., Chow L.M.L., Lambert D.M., Greenberg C.,
RA Bibeau C., Mamer O.A., Treacy E.P.;
RT "Trimethylaminuria is caused by mutations of the FMO3 gene in a North
RT American cohort.";
RL Mol. Genet. Metab. 68:24-31(1999).
RN [19]
RP VARIANTS TMAU SER-61; LEU-153; ILE-434 AND TRP-492, AND CHARACTERIZATION OF
RP VARIANTS TMAU SER-61; LEU-153; ILE-434 AND TRP-492.
RX PubMed=11191884; DOI=10.1097/00008571-200012000-00005;
RA Dolphin C.T., Janmohamed A., Smith R.L., Shephard E.A., Phillips I.R.;
RT "Compound heterozygosity for missense mutations in the flavin-containing
RT monooxygenase 3 (FM03) gene in patients with fish-odour syndrome.";
RL Pharmacogenetics 10:799-807(2000).
RN [20]
RP VARIANTS HIS-132; LYS-158; MET-257; PRO-360; GLN-362 AND ARG-503.
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 [21]
RP VARIANTS GLU-198 AND CYS-205.
RX PubMed=15618753; DOI=10.2133/dmpk.18.333;
RA Fujieda M., Yamazaki H., Togashi M., Saito T., Kamataki T.;
RT "Two novel single nucleotide polymorphisms (SNPs) of the FMO3 gene in
RT Japanese.";
RL Drug Metab. Pharmacokinet. 18:333-335(2003).
RN [22]
RP VARIANT TMAU LYS-32.
RX PubMed=12893987; DOI=10.1097/01.fpc.0000054107.48725.ce;
RA Zhang J., Tran Q., Lattard V., Cashman J.R.;
RT "Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene
RT causing trimethylaminuria.";
RL Pharmacogenetics 13:495-500(2003).
RN [23]
RP VARIANTS ASP-24; LYS-61; LYS-158; MET-257; GLY-308 AND ASN-416,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND CHARACTERIZATION OF VARIANTS ASP-24;
RP LYS-61 AND ASN-416.
RX PubMed=17050781; DOI=10.1124/jpet.106.112268;
RA Koukouritaki S.B., Poch M.T., Henderson M.C., Siddens L.K., Krueger S.K.,
RA VanDyke J.E., Williams D.E., Pajewski N.M., Wang T., Hines R.N.;
RT "Identification and functional analysis of common human flavin-containing
RT monooxygenase 3 genetic variants.";
RL J. Pharmacol. Exp. Ther. 320:266-273(2007).
CC -!- FUNCTION: Essential hepatic enzyme that catalyzes the oxygenation of a
CC wide variety of nitrogen- and sulfur-containing compounds including
CC drugs as well as dietary compounds (PubMed:10759686, PubMed:30381441).
CC Plays an important role in the metabolism of trimethylamine (TMA), via
CC the production of trimethylamine N-oxide (TMAO) metabolite
CC (PubMed:9776311). TMA is generated by the action of gut microbiota
CC using dietary precursors such as choline, choline containing compounds,
CC betaine or L-carnitine. By regulating TMAO concentration, FMO3 directly
CC impacts both platelet responsiveness and rate of thrombus formation
CC (PubMed:29981269). {ECO:0000250|UniProtKB:P97501,
CC ECO:0000269|PubMed:10759686, ECO:0000269|PubMed:29981269,
CC ECO:0000269|PubMed:30381441, ECO:0000269|PubMed:9224773,
CC ECO:0000269|PubMed:9776311}.
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 Evidence={ECO:0000269|PubMed:9536088};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NADPH + O2 + trimethylamine = H2O + NADP(+) + trimethylamine
CC N-oxide; Xref=Rhea:RHEA:31979, ChEBI:CHEBI:15377, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:15724, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:58389; EC=1.14.13.148;
CC Evidence={ECO:0000269|PubMed:9536088, ECO:0000269|PubMed:9776311};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=fenbendazole + O2 + reduced [NADPH--hemoprotein reductase] =
CC fenbendazole S-oxide + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:55928, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:35812, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:77092; EC=1.14.14.73;
CC Evidence={ECO:0000269|PubMed:10759686};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=albendazole + O2 + reduced [NADPH--hemoprotein reductase] =
CC albendazole S-oxide + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:55924, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16664, ChEBI:CHEBI:16959, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; EC=1.14.14.73;
CC Evidence={ECO:0000269|PubMed:10759686};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-nicotine + NADPH + O2 = H2O + NADP(+) + trans-(S)-nicotine
CC N(1')-oxide; Xref=Rhea:RHEA:58720, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:59806, ChEBI:CHEBI:142660;
CC Evidence={ECO:0000269|PubMed:30381441};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=21 uM for trimethylamine (at pH 8.5) {ECO:0000269|PubMed:17050781,
CC ECO:0000269|PubMed:17531949};
CC KM=31 uM for trimethylamine (at pH 7.4 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:17050781, ECO:0000269|PubMed:17531949};
CC KM=43 uM for benzydamine (at pH 7.4 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:17050781, ECO:0000269|PubMed:17531949};
CC KM=55.7 uM for ethylenethiourea (at pH 8.5)
CC {ECO:0000269|PubMed:17050781, ECO:0000269|PubMed:17531949};
CC KM=71.8 uM for methimazole (at pH 8.5) {ECO:0000269|PubMed:17050781,
CC ECO:0000269|PubMed:17531949};
CC KM=150.1 uM for sulindac (at pH 8.5) {ECO:0000269|PubMed:17050781,
CC ECO:0000269|PubMed:17531949};
CC KM=248 uM for methyl p-tolyl sulfide (at pH 7.4 and 37 degrees
CC Celsius) {ECO:0000269|PubMed:17050781, ECO:0000269|PubMed:17531949};
CC -!- INTERACTION:
CC P31513; Q8IUN9: CLEC10A; NbExp=3; IntAct=EBI-12361463, EBI-2873246;
CC P31513; O43889-2: CREB3; NbExp=4; IntAct=EBI-12361463, EBI-625022;
CC P31513; Q9NTJ5: SACM1L; NbExp=3; IntAct=EBI-12361463, EBI-3917235;
CC P31513; Q96HU1: SGSM3; NbExp=3; IntAct=EBI-12361463, EBI-7362971;
CC -!- SUBCELLULAR LOCATION: Microsome membrane
CC {ECO:0000250|UniProtKB:P32417}; Single-pass membrane protein
CC {ECO:0000255}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P32417}; Single-pass membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Liver.
CC -!- DISEASE: Trimethylaminuria (TMAU) [MIM:602079]: Inborn error of
CC metabolism associated with an offensive body odor and caused by
CC deficiency of FMO-mediated N-oxidation of amino-trimethylamine (TMA)
CC derived from foodstuffs. Affected individuals excrete relatively large
CC amounts of TMA in their urine, sweat, and breath, and exhibit a fishy
CC body odor characteristic of the malodorous free amine.
CC {ECO:0000269|PubMed:10338091, ECO:0000269|PubMed:10479479,
CC ECO:0000269|PubMed:11191884, ECO:0000269|PubMed:12893987,
CC ECO:0000269|PubMed:17531949, ECO:0000269|PubMed:9536088}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the FMO family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/fmo3/";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=A case for discomfort
CC - Issue 149 of June 2013;
CC URL="https://web.expasy.org/spotlight/back_issues/149";
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DR EMBL; M83772; AAA86284.1; -; mRNA.
DR EMBL; Z47552; CAA87632.1; -; mRNA.
DR EMBL; U39967; AAC51932.1; -; Genomic_DNA.
DR EMBL; U39961; AAC51932.1; JOINED; Genomic_DNA.
DR EMBL; U39962; AAC51932.1; JOINED; Genomic_DNA.
DR EMBL; U39963; AAC51932.1; JOINED; Genomic_DNA.
DR EMBL; U39964; AAC51932.1; JOINED; Genomic_DNA.
DR EMBL; U39965; AAC51932.1; JOINED; Genomic_DNA.
DR EMBL; U39966; AAC51932.1; JOINED; Genomic_DNA.
DR EMBL; AY895830; AAW65372.1; -; Genomic_DNA.
DR EMBL; AK313197; BAG36013.1; -; mRNA.
DR EMBL; AL021026; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471067; EAW90887.1; -; Genomic_DNA.
DR EMBL; BC032016; AAH32016.1; -; mRNA.
DR CCDS; CCDS1292.1; -.
DR PIR; A38228; A38228.
DR PIR; S62367; S51130.
DR RefSeq; NP_001002294.1; NM_001002294.2.
DR RefSeq; NP_001306102.1; NM_001319173.1.
DR RefSeq; NP_001306103.1; NM_001319174.1.
DR RefSeq; NP_008825.4; NM_006894.5.
DR AlphaFoldDB; P31513; -.
DR SMR; P31513; -.
DR BioGRID; 108615; 5.
DR IntAct; P31513; 4.
DR STRING; 9606.ENSP00000356729; -.
DR ChEMBL; CHEMBL3430864; -.
DR DrugBank; DB00918; Almotriptan.
DR DrugBank; DB00501; Cimetidine.
DR DrugBank; DB00363; Clozapine.
DR DrugBank; DB00250; Dapsone.
DR DrugBank; DB01254; Dasatinib.
DR DrugBank; DB12500; Fedratinib.
DR DrugBank; DB12265; Fexinidazole.
DR DrugBank; DB11886; Infigratinib.
DR DrugBank; DB00763; Methimazole.
DR DrugBank; DB11828; Neratinib.
DR DrugBank; DB00334; Olanzapine.
DR DrugBank; DB00768; Olopatadine.
DR DrugBank; DB12278; Propiverine.
DR DrugBank; DB15305; Risdiplam.
DR DrugBank; DB00675; Tamoxifen.
DR DrugBank; DB13609; Umifenovir.
DR DrugBank; DB05294; Vandetanib.
DR DrugBank; DB00582; Voriconazole.
DR iPTMnet; P31513; -.
DR PhosphoSitePlus; P31513; -.
DR BioMuta; FMO3; -.
DR DMDM; 6166183; -.
DR jPOST; P31513; -.
DR MassIVE; P31513; -.
DR PaxDb; P31513; -.
DR PeptideAtlas; P31513; -.
DR PRIDE; P31513; -.
DR ProteomicsDB; 54793; -.
DR Antibodypedia; 2219; 367 antibodies from 32 providers.
DR DNASU; 2328; -.
DR Ensembl; ENST00000367755.9; ENSP00000356729.4; ENSG00000007933.13.
DR GeneID; 2328; -.
DR KEGG; hsa:2328; -.
DR MANE-Select; ENST00000367755.9; ENSP00000356729.4; NM_001002294.3; NP_001002294.1.
DR UCSC; uc001ghi.3; human.
DR CTD; 2328; -.
DR DisGeNET; 2328; -.
DR GeneCards; FMO3; -.
DR GeneReviews; FMO3; -.
DR HGNC; HGNC:3771; FMO3.
DR HPA; ENSG00000007933; Tissue enriched (liver).
DR MalaCards; FMO3; -.
DR MIM; 136132; gene.
DR MIM; 602079; phenotype.
DR neXtProt; NX_P31513; -.
DR OpenTargets; ENSG00000007933; -.
DR Orphanet; 35056; NON RARE IN EUROPE: Trimethylaminuria.
DR Orphanet; 468726; Severe primary trimethylaminuria.
DR PharmGKB; PA166; -.
DR VEuPathDB; HostDB:ENSG00000007933; -.
DR eggNOG; KOG1399; Eukaryota.
DR GeneTree; ENSGT00940000161339; -.
DR HOGENOM; CLU_006909_8_2_1; -.
DR InParanoid; P31513; -.
DR OMA; SIPWLFL; -.
DR OrthoDB; 405736at2759; -.
DR PhylomeDB; P31513; -.
DR TreeFam; TF105285; -.
DR BioCyc; MetaCyc:HS00223-MON; -.
DR BRENDA; 1.14.13.148; 2681.
DR BRENDA; 1.14.13.8; 2681.
DR PathwayCommons; P31513; -.
DR Reactome; R-HSA-217271; FMO oxidises nucleophiles.
DR Reactome; R-HSA-5579019; Defective FMO3 causes TMAU.
DR SABIO-RK; P31513; -.
DR SignaLink; P31513; -.
DR BioGRID-ORCS; 2328; 5 hits in 1067 CRISPR screens.
DR ChiTaRS; FMO3; human.
DR GeneWiki; Flavin_containing_monooxygenase_3; -.
DR GenomeRNAi; 2328; -.
DR Pharos; P31513; Tbio.
DR PRO; PR:P31513; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P31513; protein.
DR Bgee; ENSG00000007933; Expressed in right lobe of liver and 121 other tissues.
DR ExpressionAtlas; P31513; baseline and differential.
DR Genevisible; P31513; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; TAS:ProtInc.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IBA:GO_Central.
DR GO; GO:0004499; F:N,N-dimethylaniline monooxygenase activity; IEA:UniProtKB-EC.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR GO; GO:0034899; F:trimethylamine monooxygenase activity; IEA:UniProtKB-EC.
DR Gene3D; 3.50.50.60; -; 2.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR000960; Flavin_mOase.
DR InterPro; IPR020946; Flavin_mOase-like.
DR InterPro; IPR002255; Flavin_mOase_3.
DR Pfam; PF00743; FMO-like; 1.
DR PIRSF; PIRSF000332; FMO; 1.
DR PRINTS; PR00370; FMOXYGENASE.
DR PRINTS; PR01123; FMOXYGENASE3.
DR SUPFAM; SSF51905; SSF51905; 2.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Disease variant; Endoplasmic reticulum; FAD;
KW Flavoprotein; Membrane; Microsome; Monooxygenase; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:9224773"
FT CHAIN 2..532
FT /note="Dimethylaniline monooxygenase [N-oxide-forming] 3"
FT /id="PRO_0000147654"
FT TRANSMEM 510..530
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 61..62
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
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 MOD_RES 401
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97501"
FT VARIANT 24
FT /note="E -> D (modest increase in catalytic efficiency
FT toward trimethylamine, methimazole, ethylenethiourea and
FT sulindac)"
FT /evidence="ECO:0000269|PubMed:17050781"
FT /id="VAR_042705"
FT VARIANT 32
FT /note="E -> K (in TMAU; dbSNP:rs72549320)"
FT /evidence="ECO:0000269|PubMed:12893987"
FT /id="VAR_037306"
FT VARIANT 52
FT /note="A -> T (in TMAU; dbSNP:rs72549321)"
FT /evidence="ECO:0000269|PubMed:10479479"
FT /id="VAR_008146"
FT VARIANT 61
FT /note="N -> K (loss of activity)"
FT /evidence="ECO:0000269|PubMed:17050781"
FT /id="VAR_042706"
FT VARIANT 61
FT /note="N -> S (in TMAU; more than 90% reduction in
FT catalytic efficiency toward trimethylamine, benzydamine and
FT methyl p-tolyl sulfide; dbSNP:rs72549322)"
FT /evidence="ECO:0000269|PubMed:11191884,
FT ECO:0000269|PubMed:17531949"
FT /id="VAR_037307"
FT VARIANT 66
FT /note="M -> I (in TMAU; loss of activity; affects FAD
FT binding; dbSNP:rs72549323)"
FT /evidence="ECO:0000269|PubMed:10338091,
FT ECO:0000269|PubMed:17531949, ECO:0000269|PubMed:9536088"
FT /id="VAR_002423"
FT VARIANT 132
FT /note="D -> H (in dbSNP:rs12072582)"
FT /evidence="ECO:0000269|PubMed:12527699, ECO:0000269|Ref.4"
FT /id="VAR_015364"
FT VARIANT 153
FT /note="P -> L (in TMAU; 90% reduction in catalytic
FT efficiency toward trimethylamine and benzydamine; 34%
FT reduction in catalytic efficiency toward methyl p-tolyl
FT sulfide; nearly no effect on affinity for these substrates;
FT dbSNP:rs72549326)"
FT /evidence="ECO:0000269|PubMed:11191884,
FT ECO:0000269|PubMed:17531949, ECO:0000269|PubMed:9536088"
FT /id="VAR_002424"
FT VARIANT 158
FT /note="E -> K (35%, 45% and 71% increase in catalytic
FT efficiency toward trimethylamine, benzydamine and methyl p-
FT tolyl sulfide, respectively; dbSNP:rs2266782)"
FT /evidence="ECO:0000269|PubMed:10479479,
FT ECO:0000269|PubMed:12527699, ECO:0000269|PubMed:17050781,
FT ECO:0000269|PubMed:17531949, ECO:0000269|PubMed:9536088,
FT ECO:0000269|Ref.4"
FT /id="VAR_002425"
FT VARIANT 198
FT /note="D -> E (in dbSNP:rs529940450)"
FT /evidence="ECO:0000269|PubMed:15618753"
FT /id="VAR_018345"
FT VARIANT 205
FT /note="R -> C (in dbSNP:rs28363549)"
FT /evidence="ECO:0000269|PubMed:15618753, ECO:0000269|Ref.4"
FT /id="VAR_018346"
FT VARIANT 257
FT /note="V -> M (65% increase in catalytic efficiency toward
FT trimethylamine and 60% reduction toward benzydamine and
FT methyl p-tolyl sulfide; dbSNP:rs1736557)"
FT /evidence="ECO:0000269|PubMed:12527699,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17050781,
FT ECO:0000269|PubMed:17531949, ECO:0000269|PubMed:9536088,
FT ECO:0000269|Ref.4"
FT /id="VAR_002426"
FT VARIANT 277
FT /note="V -> A (in dbSNP:rs2066530)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_014845"
FT VARIANT 308
FT /note="E -> G (16% reduction in catalytic efficiency toward
FT trimethylamine and 40% increase toward benzydamine and
FT methyl p-tolyl sulfide; dbSNP:rs2266780)"
FT /evidence="ECO:0000269|PubMed:10479479,
FT ECO:0000269|PubMed:17050781, ECO:0000269|PubMed:17531949,
FT ECO:0000269|PubMed:9536088, ECO:0000269|Ref.4"
FT /id="VAR_002427"
FT VARIANT 360
FT /note="L -> P (in dbSNP:rs28363581)"
FT /evidence="ECO:0000269|PubMed:12527699, ECO:0000269|Ref.4"
FT /id="VAR_015365"
FT VARIANT 362
FT /note="E -> Q (in dbSNP:rs2066532)"
FT /evidence="ECO:0000269|PubMed:12527699, ECO:0000269|Ref.4"
FT /id="VAR_014846"
FT VARIANT 387
FT /note="R -> L (in TMAU; dbSNP:rs72549331)"
FT /evidence="ECO:0000269|PubMed:10479479"
FT /id="VAR_008147"
FT VARIANT 416
FT /note="K -> N (2-fold decrease in affinity for
FT trimethylamine; 3-fold decrease in catalytic efficiency
FT toward methimazole; 3-fold increase in catalytic efficiency
FT toward sulindac; 30% increase in catalytic efficiency
FT toward ethylenethiourea; dbSNP:rs774785217)"
FT /evidence="ECO:0000269|PubMed:17050781"
FT /id="VAR_042707"
FT VARIANT 434
FT /note="M -> I (in TMAU; profoundly alters enzyme function;
FT dbSNP:rs72549332)"
FT /evidence="ECO:0000269|PubMed:11191884"
FT /id="VAR_037308"
FT VARIANT 492
FT /note="R -> W (in TMAU; loss of activity; affects FAD
FT binding; dbSNP:rs72549334)"
FT /evidence="ECO:0000269|PubMed:10338091,
FT ECO:0000269|PubMed:11191884, ECO:0000269|PubMed:17531949"
FT /id="VAR_008145"
FT VARIANT 503
FT /note="G -> R (in dbSNP:rs72549335)"
FT /evidence="ECO:0000269|PubMed:12527699"
FT /id="VAR_015366"
FT CONFLICT 298
FT /note="S -> T (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 369
FT /note="I -> L (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 400..405
FT /note="PSMEDM -> GPFYGKTL (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 410
FT /note="N -> I (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 418..419
FT /note="KW -> ANG (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 444..445
FT /note="KP -> T (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 449
FT /note="W -> M (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 454
FT /note="D -> G (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 461..462
FT /note="VY -> L (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 478
FT /note="Q -> S (in Ref. 1; AAA86284)"
FT /evidence="ECO:0000305"
FT CONFLICT 486
FT /note="I -> M (in Ref. 2; CAA87632)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 532 AA; 60033 MW; 729E41D53EFC4110 CRC64;
MGKKVAIIGA GVSGLASIRS CLEEGLEPTC FEKSNDIGGL WKFSDHAEEG RASIYKSVFS
NSSKEMMCFP DFPFPDDFPN FMHNSKIQEY IIAFAKEKNL LKYIQFKTFV SSVNKHPDFA
TTGQWDVTTE RDGKKESAVF DAVMVCSGHH VYPNLPKESF PGLNHFKGKC FHSRDYKEPG
VFNGKRVLVV GLGNSGCDIA TELSRTAEQV MISSRSGSWV MSRVWDNGYP WDMLLVTRFG
TFLKNNLPTA ISDWLYVKQM NARFKHENYG LMPLNGVLRK EPVFNDELPA SILCGIVSVK
PNVKEFTETS AIFEDGTIFE GIDCVIFATG YSFAYPFLDE SIIKSRNNEI ILFKGVFPPL
LEKSTIAVIG FVQSLGAAIP TVDLQSRWAA QVIKGTCTLP SMEDMMNDIN EKMEKKRKWF
GKSETIQTDY IVYMDELSSF IGAKPNIPWL FLTDPKLAME VYFGPCSPYQ FRLVGPGQWP
GARNAILTQW DRSLKPMQTR VVGRLQKPCF FFHWLKLFAI PILLIAVFLV LT
