ID TMLH_HUMAN Reviewed; 421 AA. AC Q9NVH6; Q5TZB5; Q6IA90; Q8TBT0; DT 20-JUN-2002, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 25-JAN-2012, entry version 91. DE RecName: Full=Trimethyllysine dioxygenase, mitochondrial; DE EC=1.14.11.8; DE AltName: Full=Epsilon-trimethyllysine 2-oxoglutarate dioxygenase; DE AltName: Full=Epsilon-trimethyllysine hydroxylase; DE AltName: Full=TML hydroxylase; DE AltName: Full=TML-alpha-ketoglutarate dioxygenase; DE Short=TML dioxygenase; DE Short=TMLD; DE Flags: Precursor; GN Name=TMLHE; Synonyms=TMLH; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RX MEDLINE=21423953; PubMed=11431483; DOI=10.1074/jbc.M105929200; RA Vaz F.M., Ofman R., Westinga K., Back J.W., Wanders R.J.A.; RT "Molecular and biochemical characterization of rat epsilon-N- RT trimethyllysine hydroxylase, the first enzyme of carnitine RT biosynthesis."; RL J. Biol. Chem. 276:33512-33517(2001). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B). RA Bechtel S., Schupp I., Duda A., Wellenreuther R., Mehrle A., RA Ruschke V., Poustka A., Wiemann S.; RL Submitted (JUL-2006) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15772651; DOI=10.1038/nature03440; RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S., RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., RA Williams G., Williams L., Williamson A., Williamson H., Wilming L., RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence of the human X chromosome."; RL Nature 434:325-337(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B). RC TISSUE=Pancreas; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, TRANSIT PEPTIDE, MUTAGENESIS RP OF HIS-389, AND ALTERNATIVE SPLICING (ISOFORMS A AND B). RX PubMed=15754339; DOI=10.1002/jcp.20332; RA Monfregola J., Cevenini A., Terracciano A., van Vlies N., Arbucci S., RA Wanders R.J., D'Urso M., Vaz F.M., Ursini M.V.; RT "Functional analysis of TMLH variants and definition of domains RT required for catalytic activity and mitochondrial targeting."; RL J. Cell. Physiol. 204:839-847(2005). RN [8] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-236, AND MASS SPECTROMETRY. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). CC -!- FUNCTION: Converts trimethyllysine (TML) into CC hydroxytrimethyllysine (HTML). CC -!- CATALYTIC ACTIVITY: N(6),N(6),N(6)-trimethyl-L-lysine + 2- CC oxoglutarate + O(2) = 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine CC + succinate + CO(2). CC -!- COFACTOR: Binds 1 Fe(2+) ion per subunit (By similarity). CC -!- COFACTOR: Ascorbate. CC -!- PATHWAY: Amine and polyamine biosynthesis; carnitine biosynthesis. CC -!- SUBUNIT: Homodimer (By similarity). CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=A; CC IsoId=Q9NVH6-1; Sequence=Displayed; CC Name=B; CC IsoId=Q9NVH6-2; Sequence=VSP_021579; CC Note=Lacks enzymatic activity; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed in adult and fetal CC tissues. CC -!- SIMILARITY: Belongs to the gamma-BBH/TMLD family. 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; AF373407; AAL01871.1; -; mRNA. DR EMBL; AK001589; BAA91775.1; -; mRNA. DR EMBL; CR457265; CAG33546.1; -; mRNA. DR EMBL; AM393196; CAL38074.1; -; mRNA. DR EMBL; BX276110; CAH71441.1; -; Genomic_DNA. DR EMBL; BX276110; CAH71442.1; -; Genomic_DNA. DR EMBL; BC025269; AAH25269.1; -; mRNA. DR IPI; IPI00301224; -. DR IPI; IPI00382858; -. DR RefSeq; NP_001171726.1; NM_001184797.1. DR RefSeq; NP_060666.1; NM_018196.3. DR UniGene; Hs.133321; -. DR ProteinModelPortal; Q9NVH6; -. DR SMR; Q9NVH6; 50-420. DR IntAct; Q9NVH6; 5. DR STRING; Q9NVH6; -. DR PhosphoSite; Q9NVH6; -. DR DMDM; 21542295; -. DR PRIDE; Q9NVH6; -. DR Ensembl; ENST00000334398; ENSP00000335261; ENSG00000185973. DR GeneID; 55217; -. DR KEGG; hsa:55217; -. DR UCSC; uc004fnn.1; human. DR UCSC; uc004fnp.2; human. DR CTD; 55217; -. DR GeneCards; GC0XM154719; -. DR H-InvDB; HIX0017170; -. DR HGNC; HGNC:18308; TMLHE. DR HPA; HPA034589; -. DR MIM; 300777; gene. DR neXtProt; NX_Q9NVH6; -. DR PharmGKB; PA38311; -. DR eggNOG; prNOG15662; -. DR GeneTree; ENSGT00530000063582; -. DR HOGENOM; HBG445343; -. DR HOVERGEN; HBG035650; -. DR InParanoid; Q9NVH6; -. DR OMA; LCGCYLT; -. DR OrthoDB; EOG4QRH4C; -. DR PhylomeDB; Q9NVH6; -. DR BRENDA; 1.14.11.8; 2681. DR Reactome; REACT_111217; Metabolism. DR DrugBank; DB00139; Succinic acid. DR DrugBank; DB00126; Vitamin C. DR NextBio; 59184; -. DR ArrayExpress; Q9NVH6; -. DR Bgee; Q9NVH6; -. DR CleanEx; HS_TMLHE; -. DR Genevestigator; Q9NVH6; -. DR GermOnline; ENSG00000185973; Homo sapiens. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL. DR GO; GO:0005506; F:iron ion binding; IEA:InterPro. DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:InterPro. DR GO; GO:0016702; F:oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen; IEA:UniProtKB-KW. DR GO; GO:0050353; F:trimethyllysine dioxygenase activity; TAS:Reactome. DR GO; GO:0045329; P:carnitine biosynthetic process; TAS:Reactome. DR GO; GO:0051354; P:negative regulation of oxidoreductase activity; IDA:BHF-UCL. DR InterPro; IPR010376; DUF971. DR InterPro; IPR003819; Taurine_dOase. DR InterPro; IPR012776; Trimethyllysine_dOase. DR KO; K00474; -. DR Pfam; PF06155; DUF971; 1. DR Pfam; PF02668; TauD; 1. DR TIGRFAMs; TIGR02410; Carnitine_TMLD; 1. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Carnitine biosynthesis; KW Complete proteome; Dioxygenase; Iron; Metal-binding; Mitochondrion; KW Oxidoreductase; Reference proteome; Transit peptide. FT TRANSIT 1 15 Mitochondrion. FT CHAIN 16 421 Trimethyllysine dioxygenase, FT mitochondrial. FT /FTId=PRO_0000002795. FT METAL 242 242 Iron; catalytic (By similarity). FT METAL 244 244 Iron; catalytic (By similarity). FT METAL 389 389 Iron; catalytic (By similarity). FT MOD_RES 236 236 N6-acetyllysine. FT VAR_SEQ 333 421 YNNYDRAVINTVPYDVVHRWYTAHRTLTIELRRPENEFWVK FT LKPGRVLFIDNWRVLHGRECFTGYRQLCGCYLTRDDVLNTA FT RLLGLQA -> LFKEKQNTVNRQWNSSLQCDIPERILTYRH FT FVSGTSIEHRGSLI (in isoform B). FT /FTId=VSP_021579. FT MUTAGEN 389 389 H->L: No catalytic activity. FT CONFLICT 66 66 N -> D (in Ref. 3; CAG33546). SQ SEQUENCE 421 AA; 49518 MW; 4E55DF349B866B43 CRC64; MWYHRLSHLH SRLQDLLKGG VIYPALPQPN FKSLLPLAVH WHHTASKSLT CAWQQHEDHF ELKYANTVMR FDYVWLRDHC RSASCYNSKT HQRSLDTASV DLCIKPKTIR LDETTLFFTW PDGHVTKYDL NWLVKNSYEG QKQKVIQPRI LWNAEIYQQA QVPSVDCQSF LETNEGLKKF LQNFLLYGIA FVENVPPTQE HTEKLAERIS LIRETIYGRM WYFTSDFSRG DTAYTKLALD RHTDTTYFQE PCGIQVFHCL KHEGTGGRTL LVDGFYAAEQ VLQKAPEEFE LLSKVPLKHE YIEDVGECHN HMIGIGPVLN IYPWNKELYL IRYNNYDRAV INTVPYDVVH RWYTAHRTLT IELRRPENEF WVKLKPGRVL FIDNWRVLHG RECFTGYRQL CGCYLTRDDV LNTARLLGLQ A //