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   03-NOV-2009, entry version 87.
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 MDS 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 MDS 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 MDS MET-108 AND LYS-192, AND CHARACTERIZATION OF VARIANTS MDS
RP   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 MDS 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 myopathic mitochondrial DNA
CC       depletion syndrome (MDS) [MIM:609560]. MDS is a clinically
CC       heterogeneous group of disorders characterized by a reduction in
CC       mitochondrial DNA (mtDNA) copy number. Primary mtDNA depletion is
CC       inherited as an autosomal recessive trait and may affect single
CC       organs, typically muscle or liver, or multiple tissues. The
CC       myopathic form of mtDNA depletion syndrome is a slowly progressive
CC       mitochondrial disorder starting in childhood and associated with
CC       less severe depletion of mtDNA in skeletal muscle (66 to 86%)
CC       compared to the hepatocerebral form of mtDNA depletion syndrome
CC       which shows up to 99% mtDNA depletion in liver.
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";
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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   UniGene; Hs.512619; -.
DR   HSSP; Q9XZT6; 1OT3.
DR   STRING; O00142; -.
DR   PRIDE; O00142; -.
DR   Ensembl; ENST00000299697; ENSP00000299697; ENSG00000166548; Homo sapiens.
DR   Ensembl; ENST00000417693; ENSP00000407469; ENSG00000166548; Homo sapiens.
DR   Ensembl; ENST00000451102; ENSP00000414334; ENSG00000166548; Homo sapiens.
DR   GeneCards; GC16M065102; -.
DR   H-InvDB; HIX0013113; -.
DR   H-InvDB; HIX0021286; -.
DR   HGNC; HGNC:11831; TK2.
DR   MIM; 188250; gene.
DR   MIM; 609560; phenotype.
DR   Orphanet; 35698; Mitochondrial DNA depletion syndrome.
DR   PharmGKB; PA134884391; -.
DR   HOVERGEN; O00142; -.
DR   BRENDA; 2.7.1.21; 247.
DR   Reactome; REACT_152; Cell Cycle, Mitotic.
DR   Reactome; REACT_1698; Metablism of nucleotides.
DR   ArrayExpress; O00142; -.
DR   Bgee; O00142; -.
DR   CleanEx; HS_TK2; -.
DR   Genevestigator; O00142; -.
DR   GermOnline; ENSG00000166548; Homo sapiens.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004797; F:thymidine kinase activity; TAS:ProtInc.
DR   GO; GO:0006260; P:DNA replication; IEA:UniProtKB-KW.
DR   PANTHER; PTHR10513; dNK; 1.
DR   Pfam; PF01712; 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; Transferase; Transit peptide.
FT   TRANSIT       1     33       Mitochondrion.
FT   CHAIN        34    265       Thymidine kinase 2, mitochondrial.
FT                                /FTId=PRO_0000016842.
FT   NP_BIND      57     64       ATP (Potential).
FT   VAR_SEQ       1     41       MLLWPLRGWAARALRCFGPGSRGSPASGPGPRRVQRRAWPP
FT                                -> MGAFCQRPSS (in isoform Short).
FT                                /FTId=VSP_003028.
FT   VARIANT      53     53       I -> M (in MDS).
FT                                /FTId=VAR_019419.
FT   VARIANT      64     64       T -> M (in MDS).
FT                                /FTId=VAR_023790.
FT   VARIANT     108    108       T -> M (in MDS; reduction of activity).
FT                                /FTId=VAR_019420.
FT   VARIANT     121    121       H -> N (in MDS).
FT                                /FTId=VAR_019421.
FT   VARIANT     183    183       R -> W (in MDS).
FT                                /FTId=VAR_023791.
FT   VARIANT     192    192       R -> K (in MDS; reduction of activity).
FT                                /FTId=VAR_023792.
FT   VARIANT     212    212       I -> N (in MDS).
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
//