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 27-MAR-2024, entry version 216. DE RecName: Full=Flavin-containing monooxygenase 3 {ECO:0000305|PubMed:10759686, ECO:0000305|PubMed:9536088}; DE EC=1.14.13.148 {ECO:0000269|PubMed:9536088, ECO:0000269|PubMed:9776311}; DE EC=1.14.13.32 {ECO:0000269|PubMed:10759686}; DE EC=1.14.13.8 {ECO:0000269|PubMed:32156684, ECO:0000269|PubMed:9536088}; DE AltName: Full=Dimethylaniline monooxygenase [N-oxide-forming] 3; 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; 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 FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=32156684; DOI=10.1124/dmd.119.089995; RA Veeravalli S., Phillips I.R., Freire R.T., Varshavi D., Everett J.R., RA Shephard E.A.; RT "Flavin-Containing Monooxygenase 1 Catalyzes the Production of Taurine from RT Hypotaurine."; RL Drug Metab. Dispos. 48:378-385(2020). RN [18] 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 [19] 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 [20] 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 [21] 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 [22] 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 [23] 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 [24] 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 PubMed:32156684). Plays an important role in the metabolism of CC trimethylamine (TMA), via the production of trimethylamine N-oxide CC (TMAO) metabolite (PubMed:9776311). TMA is generated by the action of CC gut microbiota using dietary precursors such as choline, choline CC containing compounds, betaine or L-carnitine. By regulating TMAO CC concentration, FMO3 directly impacts both platelet responsiveness and CC rate of thrombus formation (PubMed:29981269). CC {ECO:0000269|PubMed:10759686, ECO:0000269|PubMed:29981269, CC ECO:0000269|PubMed:30381441, ECO:0000269|PubMed:32156684, CC ECO:0000269|PubMed:9224773, ECO:0000269|PubMed:9776311}. 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 PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31980; CC Evidence={ECO:0000269|PubMed:9536088}; 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 PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24469; CC Evidence={ECO:0000305|PubMed:9536088}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+) + hypotaurine + NADPH + O2 = H2O + NADP(+) + taurine; CC Xref=Rhea:RHEA:69819, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57783, ChEBI:CHEBI:57853, CC ChEBI:CHEBI:58349, ChEBI:CHEBI:507393; EC=1.14.13.8; CC Evidence={ECO:0000269|PubMed:32156684}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69820; CC Evidence={ECO:0000305|PubMed:32156684}; 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 PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58721; CC Evidence={ECO:0000305|PubMed:30381441}; CC -!- CATALYTIC ACTIVITY: CC Reaction=albendazole + H(+) + NADPH + O2 = albendazole S-oxide + H2O + CC NADP(+); Xref=Rhea:RHEA:10796, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16664, ChEBI:CHEBI:16959, CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.14.13.32; CC Evidence={ECO:0000269|PubMed:10759686}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10797; CC Evidence={ECO:0000305|PubMed:10759686}; 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"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 9606-ENSP00000356729; -. DR PeptideAtlas; P31513; -. DR ProteomicsDB; 54793; -. DR Antibodypedia; 2219; 399 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 AGR; HGNC:3771; -. 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; DCYERET; -. DR OrthoDB; 2079054at2759; -. DR PhylomeDB; P31513; -. DR TreeFam; TF105285; -. DR BioCyc; MetaCyc:HS00223-MONOMER; -. 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 1147 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 122 other cell types or tissues. DR ExpressionAtlas; P31513; baseline and differential. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; TAS:ProtInc. DR GO; GO:0047638; F:albendazole monooxygenase activity; IEA:RHEA. DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro. DR GO; GO:0047822; F:hypotaurine dehydrogenase activity; IDA:UniProtKB. 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:0034899; F:trimethylamine monooxygenase activity; IEA:UniProtKB-EC. DR GO; GO:0042412; P:taurine biosynthetic process; IDA:UniProtKB. DR Gene3D; 3.50.50.60; FAD/NAD(P)-binding domain; 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 PANTHER; PTHR23023; DIMETHYLANILINE MONOOXYGENASE; 1. DR PANTHER; PTHR23023:SF44; DIMETHYLANILINE MONOOXYGENASE [N-OXIDE-FORMING] 3; 1. DR Pfam; PF00743; FMO-like; 1. DR PIRSF; PIRSF000332; FMO; 1. DR PRINTS; PR00370; FMOXYGENASE. DR PRINTS; PR01123; FMOXYGENASE3. DR SUPFAM; SSF51905; FAD/NAD(P)-binding domain; 2. DR Genevisible; P31513; HS. 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="Flavin-containing monooxygenase 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 FT p-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 //