ID TOMT_HUMAN Reviewed; 291 AA. AC Q8WZ04; B7Z816; DT 25-NOV-2008, integrated into UniProtKB/Swiss-Prot. DT 14-APR-2009, sequence version 3. DT 27-MAR-2024, entry version 133. DE RecName: Full=Transmembrane O-methyltransferase {ECO:0000305}; DE EC=2.1.1.6 {ECO:0000250|UniProtKB:A1Y9I9}; DE AltName: Full=Catechol O-methyltransferase 2 {ECO:0000303|PubMed:18794526}; DE AltName: Full=Protein LRTOMT2 {ECO:0000303|PubMed:18953341}; GN Name=TOMT {ECO:0000312|HGNC:HGNC:55527}; GN Synonyms=COMT2 {ECO:0000303|PubMed:18794526}, LRTOMT GN {ECO:0000303|PubMed:18953341}; ORFNames=PP7517; 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] (ISOFORMS 1 AND 2), AND VARIANTS DFNB63 GLN-81; RP ARG-105 AND LYS-110. RC TISSUE=Brain; RX PubMed=18953341; DOI=10.1038/ng.245; RA Ahmed Z.M., Masmoudi S., Kalay E., Belyantseva I.A., Mosrati M.A., RA Collin R.W.J., Riazuddin S., Hmani-Aifa M., Venselaar H., Kawar M.N., RA Tlili A., van der Zwaag B., Khan S.Y., Ayadi L., Riazuddin S.A., RA Morell R.J., Griffith A.J., Charfedine I., Caylan R., Oostrik J., RA Karaguzel A., Ghorbel A., Riazuddin S., Friedman T.B., Ayadi H., Kremer H.; RT "Mutations of LRTOMT, a fusion gene with alternative reading frames, cause RT nonsyndromic deafness in humans."; RL Nat. Genet. 40:1335-1340(2008). RN [2] {ECO:0000312|EMBL:AAL55772.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RX PubMed=15498874; DOI=10.1073/pnas.0404089101; RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H., Qiu X., RA Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y., Shu H., Chen X., RA Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S., Gu J.; RT "Large-scale cDNA transfection screening for genes related to cancer RT development and progression."; RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [5] {ECO:0000305} RP IDENTIFICATION, FUNCTION, VARIANT GLN-208, AND VARIANTS DFNB63 PRO-16 AND RP HIS-158. RX PubMed=18794526; DOI=10.1073/pnas.0807219105; RA Du X., Schwander M., Moresco E.M.Y., Viviani P., Haller C., RA Hildebrand M.S., Pak K., Tarantino L., Roberts A., Richardson H., Koob G., RA Najmabadi H., Ryan A.F., Smith R.J.H., Mueller U., Beutler B.; RT "A catechol-O-methyltransferase that is essential for auditory function in RT mice and humans."; RL Proc. Natl. Acad. Sci. U.S.A. 105:14609-14614(2008). RN [6] RP SUBCELLULAR LOCATION. RX PubMed=28504928; DOI=10.7554/elife.24318; RA Cunningham C.L., Wu Z., Jafari A., Zhao B., Schrode K., Harkins-Perry S., RA Lauer A., Mueller U.; RT "The murine catecholamine methyltransferase mTOMT is essential for RT mechanotransduction by cochlear hair cells."; RL Elife 6:0-0(2017). RN [7] RP VARIANT DFNB63 TRP-52. RX PubMed=28281779; DOI=10.1089/gtmb.2016.0328; RA Wang R., Han S., Khan A., Zhang X.; RT "Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or RT Syndromic Hearing Loss."; RL Genet. Test. Mol. Biomarkers 21:316-321(2017). CC -!- FUNCTION: Catalyzes the O-methylation, and thereby the inactivation, of CC catecholamine neurotransmitters and catechol hormones (By similarity). CC Required for auditory function (PubMed:18794526). Component of the CC cochlear hair cell's mechanotransduction (MET) machinery. Involved in CC the assembly of the asymmetric tip-link MET complex. Required for CC transportation of TMC1 and TMC2 proteins into the mechanically CC sensitive stereocilia of the hair cells. The function in MET is CC independent of the enzymatic activity (By similarity). CC {ECO:0000250|UniProtKB:A1Y9I9, ECO:0000269|PubMed:18794526}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a catechol + S-adenosyl-L-methionine = a guaiacol + H(+) + S- CC adenosyl-L-homocysteine; Xref=Rhea:RHEA:17877, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:33566, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, CC ChEBI:CHEBI:134251; EC=2.1.1.6; CC Evidence={ECO:0000250|UniProtKB:A1Y9I9}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17878; CC Evidence={ECO:0000250|UniProtKB:A1Y9I9}; CC -!- SUBUNIT: Interacts with LHFPL5, PCDH15, TMC1, TMC2 and TMIE. Interacts CC directly with TMC1. The interaction of TOMT with TMC1 and TMC2 is CC required for the transportation of TMC1/2 into the stereocilia of hair CC cells. {ECO:0000250|UniProtKB:A1Y9I9}. CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Membrane {ECO:0000305}; Single-pass CC membrane protein {ECO:0000305}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm CC {ECO:0000269|PubMed:28504928}. Endoplasmic reticulum CC {ECO:0000250|UniProtKB:A1Y9I9}. Note=Localized to the cell body of the CC cochlear hair cells, but is not present in the stereocilia CC (PubMed:28504928). Present but not restricted to the apical cistern, CC Hensen's body and the subsurface cistern (By similarity). CC {ECO:0000250|UniProtKB:A1Y9I9, ECO:0000269|PubMed:28504928}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=D'; CC IsoId=Q8WZ04-1; Sequence=Displayed; CC Name=2; Synonyms=E'; CC IsoId=Q8WZ04-2; Sequence=VSP_036898; CC -!- DISEASE: Deafness, autosomal recessive, 63 (DFNB63) [MIM:611451]: A CC form of non-syndromic sensorineural hearing loss. Sensorineural CC deafness results from damage to the neural receptors of the inner ear, CC the nerve pathways to the brain, or the area of the brain that receives CC sound information. {ECO:0000269|PubMed:18794526, CC ECO:0000269|PubMed:18953341, ECO:0000269|PubMed:28281779}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: LRRC51 and TOMT were originally considered as CC alternative reading frames, LRTOMT1 and LRTOMT2 of the same LRTOMT gene CC in primates. {ECO:0000303|PubMed:18953341}. CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase CC superfamily. Cation-dependent O-methyltransferase family. CC {ECO:0000255|PROSITE-ProRule:PRU01019}. CC -!- SEQUENCE CAUTION: CC Sequence=AAL55772.1; Type=Frameshift; Evidence={ECO:0000305}; 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; EU627069; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; EU627070; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AF289588; AAL55772.1; ALT_FRAME; mRNA. DR EMBL; AK302772; BAH13802.1; -; mRNA. DR EMBL; AP000812; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR RefSeq; NP_001138780.1; NM_001145308.4. [Q8WZ04-1] DR RefSeq; NP_001138781.1; NM_001145309.3. [Q8WZ04-1] DR RefSeq; NP_001138782.1; NM_001145310.3. [Q8WZ04-2] DR AlphaFoldDB; Q8WZ04; -. DR SMR; Q8WZ04; -. DR BioGRID; 128624; 17. DR STRING; 9606.ENSP00000305742; -. DR PhosphoSitePlus; Q8WZ04; -. DR BioMuta; LRTOMT; -. DR DMDM; 226693615; -. DR MassIVE; Q8WZ04; -. DR PaxDb; 9606-ENSP00000305742; -. DR Antibodypedia; 82585; 7 antibodies from 1 providers. DR DNASU; 220074; -. DR GeneID; 220074; -. DR KEGG; hsa:220074; -. DR UCSC; uc010rqw.3; human. [Q8WZ04-1] DR AGR; HGNC:25033; -. DR CTD; 220074; -. DR DisGeNET; 220074; -. DR GeneCards; TOMT; -. DR HGNC; HGNC:55527; TOMT. DR HPA; ENSG00000284922; Group enriched (fallopian tube, testis). DR MalaCards; TOMT; -. DR MIM; 611451; phenotype. DR MIM; 612414; gene. DR neXtProt; NX_Q8WZ04; -. DR Orphanet; 90636; Rare autosomal recessive non-syndromic sensorineural deafness type DFNB. DR PharmGKB; PA164722133; -. DR VEuPathDB; HostDB:ENSG00000284922; -. DR eggNOG; KOG1663; Eukaryota. DR HOGENOM; CLU_050461_5_0_1; -. DR InParanoid; Q8WZ04; -. DR OMA; DLMLCEQ; -. DR OrthoDB; 4040098at2759; -. DR PhylomeDB; Q8WZ04; -. DR TreeFam; TF329140; -. DR PathwayCommons; Q8WZ04; -. DR Reactome; R-HSA-379397; Enzymatic degradation of dopamine by COMT. DR BioGRID-ORCS; 220074; 10 hits in 1151 CRISPR screens. DR ChiTaRS; LRTOMT; human. DR GenomeRNAi; 220074; -. DR Pharos; Q8WZ04; Tbio. DR PRO; PR:Q8WZ04; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q8WZ04; Protein. DR Bgee; ENSG00000184154; Expressed in right testis and 100 other cell types or tissues. DR ExpressionAtlas; Q8WZ04; differential. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0016206; F:catechol O-methyltransferase activity; ISS:UniProtKB. DR GO; GO:0102084; F:L-dopa O-methyltransferase activity; IEA:UniProtKB-EC. DR GO; GO:0102938; F:orcinol O-methyltransferase activity; IEA:UniProtKB-EC. DR GO; GO:0060117; P:auditory receptor cell development; ISS:UniProtKB. DR GO; GO:0042424; P:catecholamine catabolic process; ISS:UniProtKB. DR GO; GO:0032502; P:developmental process; IBA:GO_Central. DR GO; GO:0042420; P:dopamine catabolic process; TAS:Reactome. DR GO; GO:0042417; P:dopamine metabolic process; IBA:GO_Central. DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW. DR GO; GO:0007605; P:sensory perception of sound; ISS:UniProtKB. DR CDD; cd02440; AdoMet_MTases; 1. DR Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1. DR InterPro; IPR029063; SAM-dependent_MTases_sf. DR InterPro; IPR002935; SAM_O-MeTrfase. DR PANTHER; PTHR43836; CATECHOL O-METHYLTRANSFERASE 1-RELATED; 1. DR PANTHER; PTHR43836:SF1; TRANSMEMBRANE O-METHYLTRANSFERASE; 1. DR Pfam; PF01596; Methyltransf_3; 1. DR SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1. DR PROSITE; PS51682; SAM_OMT_I; 1. DR Genevisible; Q8WZ04; HS. PE 1: Evidence at protein level; KW Alternative splicing; Catecholamine metabolism; Cytoplasm; Deafness; KW Disease variant; Endoplasmic reticulum; Hearing; Membrane; KW Methyltransferase; Neurotransmitter degradation; Non-syndromic deafness; KW Reference proteome; S-adenosyl-L-methionine; Transferase; Transmembrane; KW Transmembrane helix. FT CHAIN 1..291 FT /note="Transmembrane O-methyltransferase" FT /id="PRO_0000354093" FT TRANSMEM 31..51 FT /note="Helical" FT /evidence="ECO:0000255" FT BINDING 137 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019" FT BINDING 139..140 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019" FT BINDING 145 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019" FT BINDING 163 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019" FT BINDING 193 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019" FT VAR_SEQ 28..67 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15498874, FT ECO:0000303|PubMed:18953341" FT /id="VSP_036898" FT VARIANT 16 FT /note="L -> P (in DFNB63; uncertain significance; FT dbSNP:rs891068154)" FT /evidence="ECO:0000269|PubMed:18794526" FT /id="VAR_047554" FT VARIANT 52 FT /note="R -> W (in DFNB63; uncertain significance; FT dbSNP:rs1372399805)" FT /evidence="ECO:0000269|PubMed:28281779" FT /id="VAR_079506" FT VARIANT 81 FT /note="R -> Q (in DFNB63; dbSNP:rs137853185)" FT /evidence="ECO:0000269|PubMed:18953341" FT /id="VAR_054955" FT VARIANT 105 FT /note="W -> R (in DFNB63; dbSNP:rs137853186)" FT /evidence="ECO:0000269|PubMed:18953341" FT /id="VAR_054956" FT VARIANT 110 FT /note="E -> K (in DFNB63; dbSNP:rs137853187)" FT /evidence="ECO:0000269|PubMed:18953341" FT /id="VAR_054957" FT VARIANT 158 FT /note="R -> H (in DFNB63; uncertain significance; FT dbSNP:rs758115449)" FT /evidence="ECO:0000269|PubMed:18794526" FT /id="VAR_047555" FT VARIANT 208 FT /note="R -> Q (in dbSNP:rs61741195)" FT /evidence="ECO:0000269|PubMed:18794526" FT /id="VAR_047556" SQ SEQUENCE 291 AA; 32155 MW; F6108CBEE0FF49E7 CRC64; MGTPWRKRKG IAGPGLPDLS CALVLQPRAQ VGTMSPAIAL AFLPLVVTLL VRYRHYFRLL VRTVLLRSLR DCLSGLRIEE RAFSYVLTHA LPGDPGHILT TLDHWSSRCE YLSHMGPVKG QILMRLVEEK APACVLELGT YCGYSTLLIA RALPPGGRLL TVERDPRTAA VAEKLIRLAG FDEHMVELIV GSSEDVIPCL RTQYQLSRAD LVLLAHRPRC YLRDLQLLEA HALLPAGATV LADHVLFPGA PRFLQYAKSC GRYRCRLHHT GLPDFPAIKD GIAQLTYAGP G //