ID KITM_HUMAN Reviewed; 265 AA. AC O00142; O15238; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 28-JUL-2009, sequence version 4. DT 25-JAN-2012, entry version 108. DE RecName: Full=Thymidine kinase 2, mitochondrial; DE EC=2.7.1.21; DE AltName: Full=Mt-TK; DE Flags: Precursor; GN Name=TK2; 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 SHORT). RC TISSUE=Liver; RX MEDLINE=97236800; PubMed=9079672; DOI=10.1074/jbc.272.13.8454; RA Johansson M., Karlsson A.; RT "Cloning of the cDNA and chromosome localization of the gene for human RT thymidine kinase 2."; RL J. Biol. Chem. 272:8454-8458(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), PROTEIN SEQUENCE OF 34-61 RP (ISOFORM LONG), AND CHARACTERIZATION. RC TISSUE=Brain; RX MEDLINE=99142705; PubMed=9989599; DOI=10.1016/S0014-5793(98)01711-6; RA Wang L., Munch-Petersen B., Herrstroem Sjoeberg A., Hellman U., RA Bergman T., Joernvall H., Eriksson S.; RT "Human thymidine kinase 2: molecular cloning and characterisation of RT the enzyme activity with antiviral and cytostatic nucleoside RT substrates."; RL FEBS Lett. 443:170-174(1999). RN [3] RP SEQUENCE REVISION. RA Wang L.; RL Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., RA Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [5] RP VARIANTS MTDPS2 ASN-121 AND ASN-212. RX MEDLINE=21547527; PubMed=11687801; DOI=10.1038/ng751; RA Saada A., Shaag A., Mandel H., Nevo Y., Eriksson S., Elpeleg O.; RT "Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion RT myopathy."; RL Nat. Genet. 29:342-344(2001). RN [6] RP VARIANTS MTDPS2 MET-53; MET-108 AND ASN-121. RX MEDLINE=22278962; PubMed=12391347; RA Mancuso M., Salviati L., Sacconi S., Otaegui D., Camano P., Marina A., RA Bacman S., Moraes C.T., Carlo J.R., Garcia M., Garcia-Alvarez M., RA Monzon L., Naini A.B., Hirano M., Bonilla E., Taratuto A.L., RA DiMauro S., Vu T.H.; RT "Mitochondrial DNA depletion: mutations in thymidine kinase gene with RT myopathy and SMA."; RL Neurology 59:1197-1202(2002). RN [7] RP VARIANTS MTDPS2 MET-108 AND LYS-192, AND CHARACTERIZATION OF VARIANTS RP MTDPS2 MET-108 AND LYS-192. RX PubMed=15639197; DOI=10.1016/j.ymgme.2004.09.005; RA Wang L., Limongelli A., Vila M.R., Carrara F., Zeviani M., RA Eriksson S.; RT "Molecular insight into mitochondrial DNA depletion syndrome in two RT patients with novel mutations in the deoxyguanosine kinase and RT thymidine kinase 2 genes."; RL Mol. Genet. Metab. 84:75-82(2005). RN [8] RP VARIANTS MTDPS2 MET-64 AND TRP-183. RX PubMed=15907288; DOI=10.1016/j.nmd.2005.03.010; RA Tulinius M., Moslemi A.-R., Darin N., Holme E., Oldfors A.; RT "Novel mutations in the thymidine kinase 2 gene (TK2) associated with RT fatal mitochondrial myopathy and mitochondrial DNA depletion."; RL Neuromuscul. Disord. 15:412-415(2005). CC -!- FUNCTION: Deoxyribonucleoside kinase that phosphorylates CC thymidine, deoxycytidine, and deoxyuridine. Also phosphorylates CC anti-viral and anti-cancer nucleoside analogs. CC -!- CATALYTIC ACTIVITY: ATP + thymidine = ADP + thymidine 5'- CC phosphate. CC -!- SUBUNIT: Monomer. CC -!- SUBCELLULAR LOCATION: Mitochondrion. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Long; CC IsoId=O00142-1; Sequence=Displayed; CC Name=Short; CC IsoId=O00142-2; Sequence=VSP_003028; CC Note=No experimental confirmation available; CC -!- TISSUE SPECIFICITY: Predominantly expressed in liver, pancreas, CC muscle, and brain. CC -!- DISEASE: Defects in TK2 are a cause of mitochondrial DNA depletion CC syndrome type 2 (MTDPS2) [MIM:609560]. A disorder characterized CC primarily by childhood onset of muscle weakness associated with CC depletion of mtDNA in skeletal muscle. There is wide clinical CC variability; some patients have onset in infancy and show a CC rapidly progressive course with early death due to respiratory CC failure, whereas others have later onset of a slowly progressive CC myopathy. CC -!- SIMILARITY: Belongs to the DCK/DGK family. CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TK2"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; U77088; AAC51167.1; -; mRNA. DR EMBL; Y10498; CAA71523.3; -; mRNA. DR EMBL; AC010542; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR IPI; IPI00215650; -. DR IPI; IPI00337439; -. DR RefSeq; NP_001166114.1; NM_001172643.1. DR RefSeq; NP_004605.4; NM_004614.4. DR UniGene; Hs.512619; -. DR ProteinModelPortal; O00142; -. DR SMR; O00142; 43-239. DR STRING; O00142; -. DR PRIDE; O00142; -. DR Ensembl; ENST00000299697; ENSP00000299697; ENSG00000166548. DR GeneID; 7084; -. DR KEGG; hsa:7084; -. DR CTD; 7084; -. DR GeneCards; GC16M066543; -. DR H-InvDB; HIX0013113; -. DR H-InvDB; HIX0021286; -. DR HGNC; HGNC:11831; TK2. DR HPA; HPA041162; -. DR MIM; 188250; gene. DR MIM; 609560; phenotype. DR neXtProt; NX_O00142; -. DR Orphanet; 254875; Mitochondrial DNA depletion syndrome, myopathic form. DR eggNOG; prNOG14767; -. DR HOVERGEN; HBG006216; -. DR InParanoid; O00142; -. DR OrthoDB; EOG4B8JF5; -. DR BRENDA; 2.7.1.21; 2681. DR Reactome; REACT_111217; Metabolism. DR Reactome; REACT_152; Cell Cycle, Mitotic. DR ArrayExpress; O00142; -. DR Bgee; O00142; -. DR CleanEx; HS_TK2; -. DR Genevestigator; O00142; -. DR GermOnline; ENSG00000166548; Homo sapiens. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016773; F:phosphotransferase activity, alcohol group as acceptor; IEA:InterPro. DR GO; GO:0004797; F:thymidine kinase activity; TAS:ProtInc. DR GO; GO:0006260; P:DNA replication; IEA:UniProtKB-KW. DR GO; GO:0006206; P:pyrimidine base metabolic process; TAS:Reactome. DR GO; GO:0043097; P:pyrimidine nucleoside salvage; TAS:Reactome. DR InterPro; IPR002624; Deoxynucleoside_kinase. DR KO; K00857; -. DR PANTHER; PTHR10513; dNK; 1. DR Pfam; PF01712; dNK; 1. DR PIRSF; PIRSF000705; DNK; 1. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Complete proteome; KW Direct protein sequencing; Disease mutation; DNA synthesis; Kinase; KW Mitochondrion; Nucleotide-binding; Reference proteome; Transferase; KW Transit peptide. FT TRANSIT 1 33 Mitochondrion. FT CHAIN 34 265 Thymidine kinase 2, mitochondrial. FT /FTId=PRO_0000016842. FT NP_BIND 57 65 ATP (By similarity). FT ACT_SITE 133 133 Proton acceptor (Potential). FT BINDING 81 81 Substrate (By similarity). FT BINDING 99 99 Substrate (By similarity). FT BINDING 110 110 Substrate (By similarity). FT BINDING 134 134 Substrate (By similarity). FT BINDING 201 201 Substrate (By similarity). FT VAR_SEQ 1 41 MLLWPLRGWAARALRCFGPGSRGSPASGPGPRRVQRRAWPP FT -> MGAFCQRPSS (in isoform Short). FT /FTId=VSP_003028. FT VARIANT 53 53 I -> M (in MTDPS2). FT /FTId=VAR_019419. FT VARIANT 64 64 T -> M (in MTDPS2). FT /FTId=VAR_023790. FT VARIANT 108 108 T -> M (in MTDPS2; reduction of FT activity). FT /FTId=VAR_019420. FT VARIANT 121 121 H -> N (in MTDPS2). FT /FTId=VAR_019421. FT VARIANT 183 183 R -> W (in MTDPS2). FT /FTId=VAR_023791. FT VARIANT 192 192 R -> K (in MTDPS2; reduction of FT activity). FT /FTId=VAR_023792. FT VARIANT 212 212 I -> N (in MTDPS2). FT /FTId=VAR_019422. FT CONFLICT 37 37 R -> Y (in Ref. 2; AA sequence). FT CONFLICT 61 61 S -> G (in Ref. 1; AAC51167). FT CONFLICT 238 238 D -> DH (in Ref. 2; CAA71523). FT CONFLICT 241 241 Missing (in Ref. 1; AAC51167). SQ SEQUENCE 265 AA; 31005 MW; 1E9CB62D0321A992 CRC64; MLLWPLRGWA ARALRCFGPG SRGSPASGPG PRRVQRRAWP PDKEQEKEKK SVICVEGNIA SGKTTCLEFF SNATDVEVLT EPVSKWRNVR GHNPLGLMYH DASRWGLTLQ TYVQLTMLDR HTRPQVSSVR LMERSIHSAR YIFVENLYRS GKMPEVDYVV LSEWFDWILR NMDVSVDLIV YLRTNPETCY QRLKKRCREE EKVIPLEYLE AIHHLHEEWL IKGSLFPMAA PVLVIEADHH MERMLELFEQ NRDRILTPEN RKHCP //