KTHY_HUMAN
ID KTHY_HUMAN Reviewed; 212 AA.
AC P23919; B7ZW70; Q6FGX1; Q9BUX4;
DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
DT 07-DEC-2004, sequence version 4.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Thymidylate kinase;
DE EC=2.7.4.9 {ECO:0000269|PubMed:12614151, ECO:0000269|PubMed:2017365, ECO:0000269|PubMed:8024690, ECO:0000305|PubMed:18469};
DE AltName: Full=dTMP kinase;
GN Name=DTYMK; Synonyms=CDC8, TMPK, TYMK;
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] (ISOFORM 1), FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=2017365; DOI=10.1093/nar/19.4.823;
RA Su J.Y., Sclafani R.A.;
RT "Molecular cloning and expression of the human deoxythymidylate kinase gene
RT in yeast.";
RL Nucleic Acids Res. 19:823-827(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY, AND
RP DEVELOPMENTAL STAGE.
RX PubMed=8024690; DOI=10.1089/dna.1994.13.461;
RA Huang S.H., Tang A., Drisco B., Zhang S.Q., Seeger R., Li C., Jong A.;
RT "Human dTMP kinase: gene expression and enzymatic activity coinciding with
RT cell cycle progression and cell growth.";
RL DNA Cell Biol. 13:461-471(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA LaBaer J.;
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] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Muscle;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, COFACTOR, AND PATHWAY.
RX PubMed=18469; DOI=10.1016/s0021-9258(17)40077-9;
RA Lee L.S., Cheng Y.;
RT "Human thymidylate kinase. Purification, characterization, and kinetic
RT behavior of the thymidylate kinase derived from chronic myelocytic
RT leukemia.";
RL J. Biol. Chem. 252:5686-5691(1977).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-169, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
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).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) IN COMPLEX WITH ADP OR ATP ANALOG
RP AND WITH THYMIDINE ANALOGS, CATALYTIC ACTIVITY, FUNCTION, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=12614151; DOI=10.1021/bi027302t;
RA Ostermann N., Segura-Pena D., Meier C., Veit T., Monnerjahn C., Konrad M.,
RA Lavie A.;
RT "Structures of human thymidylate kinase in complex with prodrugs:
RT implications for the structure-based design of novel compounds.";
RL Biochemistry 42:2568-2577(2003).
CC -!- FUNCTION: Catalyzes the phosphorylation of thymidine monophosphate
CC (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the
CC DNA building block dTTP, with ATP as the preferred phosphoryl donor in
CC the presence of Mg(2+). {ECO:0000269|PubMed:12614151,
CC ECO:0000269|PubMed:2017365, ECO:0000269|PubMed:8024690,
CC ECO:0000305|PubMed:18469}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + dTMP = ADP + dTDP; Xref=Rhea:RHEA:13517,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:58369, ChEBI:CHEBI:63528,
CC ChEBI:CHEBI:456216; EC=2.7.4.9;
CC Evidence={ECO:0000269|PubMed:12614151, ECO:0000269|PubMed:2017365,
CC ECO:0000269|PubMed:8024690, ECO:0000305|PubMed:18469};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:18469};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=12 uM for AZTMP {ECO:0000269|PubMed:12614151};
CC KM=5 uM for dTMP {ECO:0000269|PubMed:12614151};
CC -!- PATHWAY: Pyrimidine metabolism; dTTP biosynthesis.
CC {ECO:0000269|PubMed:18469}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:18469}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P23919-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P23919-2; Sequence=VSP_054164;
CC -!- DEVELOPMENTAL STAGE: The levels of dTMP kinase mRNA and its enzymatic
CC activity fluctuate during the cell cycle, peaking at the S phase.
CC {ECO:0000269|PubMed:8024690}.
CC -!- SIMILARITY: Belongs to the thymidylate kinase family. {ECO:0000305}.
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DR EMBL; X54729; CAA38528.1; -; mRNA.
DR EMBL; L16991; AAA21719.1; -; mRNA.
DR EMBL; CR541986; CAG46783.1; -; mRNA.
DR EMBL; BC001827; AAH01827.1; -; mRNA.
DR EMBL; BC171902; AAI71902.1; -; mRNA.
DR CCDS; CCDS2552.1; -. [P23919-1]
DR PIR; S26845; S26845.
DR RefSeq; NP_001158503.1; NM_001165031.1. [P23919-2]
DR RefSeq; NP_001307832.1; NM_001320903.1.
DR RefSeq; NP_036277.2; NM_012145.3. [P23919-1]
DR PDB; 1E2D; X-ray; 1.65 A; A=1-212.
DR PDB; 1E2E; X-ray; 2.00 A; A=1-212.
DR PDB; 1E2F; X-ray; 1.60 A; A=1-212.
DR PDB; 1E2G; X-ray; 1.70 A; A=1-212.
DR PDB; 1E2Q; X-ray; 1.70 A; A=1-212.
DR PDB; 1E98; X-ray; 1.90 A; A=1-212.
DR PDB; 1E99; X-ray; 1.80 A; A=1-212.
DR PDB; 1E9A; X-ray; 1.60 A; A=1-212.
DR PDB; 1E9B; X-ray; 1.70 A; A=1-212.
DR PDB; 1E9C; X-ray; 1.60 A; A=1-212.
DR PDB; 1E9D; X-ray; 1.70 A; A=1-212.
DR PDB; 1E9E; X-ray; 1.60 A; A=1-212.
DR PDB; 1E9F; X-ray; 1.90 A; A=1-144, A=149-212.
DR PDB; 1NMX; X-ray; 1.70 A; A=1-212.
DR PDB; 1NMY; X-ray; 1.60 A; A=4-212.
DR PDB; 1NMZ; X-ray; 1.75 A; A=1-212.
DR PDB; 1NN0; X-ray; 1.60 A; A=1-212.
DR PDB; 1NN1; X-ray; 1.90 A; A=1-212.
DR PDB; 1NN3; X-ray; 1.55 A; A=1-212.
DR PDB; 1NN5; X-ray; 1.50 A; A=1-212.
DR PDB; 2XX3; X-ray; 2.00 A; A=1-212.
DR PDBsum; 1E2D; -.
DR PDBsum; 1E2E; -.
DR PDBsum; 1E2F; -.
DR PDBsum; 1E2G; -.
DR PDBsum; 1E2Q; -.
DR PDBsum; 1E98; -.
DR PDBsum; 1E99; -.
DR PDBsum; 1E9A; -.
DR PDBsum; 1E9B; -.
DR PDBsum; 1E9C; -.
DR PDBsum; 1E9D; -.
DR PDBsum; 1E9E; -.
DR PDBsum; 1E9F; -.
DR PDBsum; 1NMX; -.
DR PDBsum; 1NMY; -.
DR PDBsum; 1NMZ; -.
DR PDBsum; 1NN0; -.
DR PDBsum; 1NN1; -.
DR PDBsum; 1NN3; -.
DR PDBsum; 1NN5; -.
DR PDBsum; 2XX3; -.
DR AlphaFoldDB; P23919; -.
DR SMR; P23919; -.
DR BioGRID; 108174; 54.
DR IntAct; P23919; 6.
DR MINT; P23919; -.
DR STRING; 9606.ENSP00000304802; -.
DR BindingDB; P23919; -.
DR ChEMBL; CHEMBL4388; -.
DR DrugBank; DB03150; 2',3'-Dideoxythymidine-5'-Monophosphate.
DR DrugBank; DB03233; 3'-deoxy-3'-aminothymidine monophosphate.
DR DrugBank; DB03195; 3'-Fluoro-3'-deoxythymidine 5'-monophosphate.
DR DrugBank; DB03845; P1-(5'-Adenosyl)P5-(5'-(3'azido-3'-Deoxythymidyl))Pentaphosphate.
DR DrugBank; DB03280; p1-(5'-adenosyl)p5-(5'-thymidyl)pentaphosphate.
DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester.
DR DrugBank; DB01643; Thymidine monophosphate.
DR DrugBank; DB03666; Zidovudine monophosphate.
DR DrugCentral; P23919; -.
DR GlyGen; P23919; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P23919; -.
DR PhosphoSitePlus; P23919; -.
DR SwissPalm; P23919; -.
DR BioMuta; DTYMK; -.
DR DMDM; 56405325; -.
DR EPD; P23919; -.
DR jPOST; P23919; -.
DR MassIVE; P23919; -.
DR MaxQB; P23919; -.
DR PaxDb; P23919; -.
DR PeptideAtlas; P23919; -.
DR PRIDE; P23919; -.
DR ProteomicsDB; 54165; -. [P23919-1]
DR Antibodypedia; 34572; 467 antibodies from 30 providers.
DR DNASU; 1841; -.
DR Ensembl; ENST00000305784.7; ENSP00000304802.2; ENSG00000168393.13. [P23919-1]
DR GeneID; 1841; -.
DR KEGG; hsa:1841; -.
DR MANE-Select; ENST00000305784.7; ENSP00000304802.2; NM_012145.4; NP_036277.2.
DR CTD; 1841; -.
DR DisGeNET; 1841; -.
DR GeneCards; DTYMK; -.
DR HGNC; HGNC:3061; DTYMK.
DR HPA; ENSG00000168393; Low tissue specificity.
DR MIM; 188345; gene.
DR neXtProt; NX_P23919; -.
DR OpenTargets; ENSG00000168393; -.
DR PharmGKB; PA150; -.
DR VEuPathDB; HostDB:ENSG00000168393; -.
DR eggNOG; KOG3327; Eukaryota.
DR GeneTree; ENSGT00940000154030; -.
DR InParanoid; P23919; -.
DR OMA; CYAPERG; -.
DR PhylomeDB; P23919; -.
DR TreeFam; TF324638; -.
DR BioCyc; MetaCyc:HS11626-MON; -.
DR BRENDA; 2.7.4.9; 2681.
DR PathwayCommons; P23919; -.
DR Reactome; R-HSA-499943; Interconversion of nucleotide di- and triphosphates.
DR SABIO-RK; P23919; -.
DR SignaLink; P23919; -.
DR UniPathway; UPA00575; -.
DR BioGRID-ORCS; 1841; 772 hits in 1086 CRISPR screens.
DR EvolutionaryTrace; P23919; -.
DR GeneWiki; DTYMK; -.
DR GenomeRNAi; 1841; -.
DR Pharos; P23919; Tbio.
DR PRO; PR:P23919; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P23919; protein.
DR Bgee; ENSG00000168393; Expressed in ventricular zone and 141 other tissues.
DR ExpressionAtlas; P23919; baseline and differential.
DR Genevisible; P23919; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004550; F:nucleoside diphosphate kinase activity; IBA:GO_Central.
DR GO; GO:0004798; F:thymidylate kinase activity; IDA:UniProtKB.
DR GO; GO:0009041; F:uridylate kinase activity; IBA:GO_Central.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR GO; GO:0006233; P:dTDP biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006235; P:dTTP biosynthetic process; IBA:GO_Central.
DR GO; GO:0006227; P:dUDP biosynthetic process; IBA:GO_Central.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0046105; P:thymidine biosynthetic process; IDA:UniProtKB.
DR Gene3D; 3.40.50.300; -; 1.
DR HAMAP; MF_00165; Thymidylate_kinase; 1.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR039430; Thymidylate_kin-like_dom.
DR InterPro; IPR018095; Thymidylate_kin_CS.
DR InterPro; IPR018094; Thymidylate_kinase.
DR Pfam; PF02223; Thymidylate_kin; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00041; DTMP_kinase; 1.
DR PROSITE; PS01331; THYMIDYLATE_KINASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Kinase;
KW Nucleotide biosynthesis; Nucleotide-binding; Reference proteome;
KW Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330"
FT CHAIN 2..212
FT /note="Thymidylate kinase"
FT /id="PRO_0000155210"
FT REGION 133..157
FT /note="LID"
FT /evidence="ECO:0000305|PubMed:12614151"
FT BINDING 16..21
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:12614151,
FT ECO:0007744|PDB:1NMX, ECO:0007744|PDB:1NMY,
FT ECO:0007744|PDB:1NN0, ECO:0007744|PDB:1NN3"
FT BINDING 97
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:12614151,
FT ECO:0007744|PDB:1NMY, ECO:0007744|PDB:1NMZ,
FT ECO:0007744|PDB:1NN1"
FT BINDING 182
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0007744|PDB:1NMX, ECO:0007744|PDB:1NMY,
FT ECO:0007744|PDB:1NN0, ECO:0007744|PDB:1NN3"
FT BINDING 192
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0007744|PDB:1NMY, ECO:0007744|PDB:1NMZ,
FT ECO:0007744|PDB:1NN1, ECO:0007744|PDB:1NN5"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 169
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VAR_SEQ 111..134
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054164"
FT CONFLICT 3
FT /note="A -> P (in Ref. 3; CAG46783)"
FT /evidence="ECO:0000305"
FT CONFLICT 31..37
FT /note="CAAGHRA -> SRGPPP (in Ref. 1; CAA38528)"
FT /evidence="ECO:0000305"
FT CONFLICT 58
FT /note="Q -> K (in Ref. 2; AAA21719)"
FT /evidence="ECO:0000305"
FT CONFLICT 68
FT /note="V -> A (in Ref. 3; CAG46783)"
FT /evidence="ECO:0000305"
FT CONFLICT 183..184
FT /note="SI -> RL (in Ref. 1; CAA38528)"
FT /evidence="ECO:0000305"
FT CONFLICT 190..191
FT /note="DI -> EL (in Ref. 1; CAA38528 and 2; AAA21719)"
FT /evidence="ECO:0000305"
FT STRAND 8..14
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 19..32
FT /evidence="ECO:0007829|PDB:1NN5"
FT STRAND 37..43
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 48..57
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 65..77
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 80..88
FT /evidence="ECO:0007829|PDB:1NN5"
FT STRAND 92..97
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 99..107
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 114..118
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 119..121
FT /evidence="ECO:0007829|PDB:1NN5"
FT STRAND 124..126
FT /evidence="ECO:0007829|PDB:1NN3"
FT STRAND 128..134
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 137..142
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 149..151
FT /evidence="ECO:0007829|PDB:2XX3"
FT HELIX 154..167
FT /evidence="ECO:0007829|PDB:1NN5"
FT STRAND 171..173
FT /evidence="ECO:0007829|PDB:1E2E"
FT STRAND 175..179
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 184..201
FT /evidence="ECO:0007829|PDB:1NN5"
FT HELIX 202..204
FT /evidence="ECO:0007829|PDB:1NN5"
SQ SEQUENCE 212 AA; 23819 MW; A52876625B3621B1 CRC64;
MAARRGALIV LEGVDRAGKS TQSRKLVEAL CAAGHRAELL RFPERSTEIG KLLSSYLQKK
SDVEDHSVHL LFSANRWEQV PLIKEKLSQG VTLVVDRYAF SGVAFTGAKE NFSLDWCKQP
DVGLPKPDLV LFLQLQLADA AKRGAFGHER YENGAFQERA LRCFHQLMKD TTLNWKMVDA
SKSIEAVHED IRVLSEDAIR TATEKPLGEL WK
