TOMT_HUMAN
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 03-AUG-2022, entry version 124.
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},
GN LRTOMT {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};
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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 CCDS; CCDS44668.1; -. [Q8WZ04-1]
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 PaxDb; Q8WZ04; -.
DR PeptideAtlas; Q8WZ04; -.
DR PRIDE; Q8WZ04; -.
DR DNASU; 220074; -.
DR GeneID; 220074; -.
DR KEGG; hsa:220074; -.
DR UCSC; uc010rqw.3; human. [Q8WZ04-1]
DR CTD; 220074; -.
DR DisGeNET; 220074; -.
DR GeneCards; LRTOMT; -.
DR GeneReviews; LRTOMT; -.
DR HGNC; HGNC:55527; TOMT.
DR HPA; ENSG00000284922; Group enriched (fallopian tube, testis).
DR MalaCards; LRTOMT; -.
DR MIM; 611451; phenotype.
DR MIM; 612414; gene.
DR neXtProt; NX_Q8WZ04; -.
DR Orphanet; 90636; Autosomal recessive non-syndromic sensorineural deafness type DFNB.
DR PharmGKB; PA164722133; -.
DR VEuPathDB; HostDB:ENSG00000284922; -.
DR eggNOG; KOG1663; Eukaryota.
DR GeneTree; ENSGT00940000161220; -.
DR HOGENOM; CLU_050461_5_0_1; -.
DR InParanoid; Q8WZ04; -.
DR OMA; YVLTHST; -.
DR OrthoDB; 1274244at2759; -.
DR PhylomeDB; Q8WZ04; -.
DR TreeFam; TF329140; -.
DR PathwayCommons; Q8WZ04; -.
DR Reactome; R-HSA-379397; Enzymatic degradation of dopamine by COMT.
DR BioGRID-ORCS; 220074; 9 hits in 1073 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 98 other tissues.
DR Genevisible; Q8WZ04; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0008171; F:O-methyltransferase activity; IBA:GO_Central.
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:0042135; P:neurotransmitter catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0007605; P:sensory perception of sound; ISS:UniProtKB.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR002935; SAM_O-MeTrfase.
DR InterPro; IPR033025; TOMT.
DR PANTHER; PTHR43836:SF1; PTHR43836:SF1; 1.
DR Pfam; PF01596; Methyltransf_3; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51682; SAM_OMT_I; 1.
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; unknown pathological
FT significance; dbSNP:rs891068154)"
FT /evidence="ECO:0000269|PubMed:18794526"
FT /id="VAR_047554"
FT VARIANT 52
FT /note="R -> W (in DFNB63; unknown pathological
FT significance; 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; unknown pathological
FT significance; 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
