ID CMPK2_HUMAN Reviewed; 449 AA. AC Q5EBM0; A2RUB0; A5D8T2; B7ZM18; Q6ZRU2; Q96AL8; DT 29-APR-2008, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 27-MAR-2024, entry version 139. DE RecName: Full=UMP-CMP kinase 2, mitochondrial; DE EC=2.7.4.14; DE AltName: Full=Nucleoside-diphosphate kinase; DE EC=2.7.4.6; DE Flags: Precursor; GN Name=CMPK2; 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 SUBCELLULAR LOCATION. RX PubMed=17999954; DOI=10.1074/jbc.m707997200; RA Xu Y., Johansson M., Karlsson A.; RT "Human UMP-CMP kinase 2, a novel nucleoside monophosphate kinase localized RT in mitochondria."; RL J. Biol. Chem. 283:1563-1571(2008). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4), AND NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 9-449 (ISOFORM 1). RC TISSUE=Lymph, and Prostate; 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 [4] 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 [5] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=23416111; DOI=10.1016/j.biocel.2013.02.004; RA Amiri M., Conserva F., Panayiotou C., Karlsson A., Solaroli N.; RT "The human adenylate kinase 9 is a nucleoside mono- and diphosphate RT kinase."; RL Int. J. Biochem. Cell Biol. 45:925-931(2013). RN [6] RP FUNCTION, AND INDUCTION BY INTERFERON-ALPHA. RX PubMed=30083606; DOI=10.1126/sciadv.aat0843; RA El-Diwany R., Soliman M., Sugawara S., Breitwieser F., Skaist A., RA Coggiano C., Sangal N., Chattergoon M., Bailey J.R., Siliciano R.F., RA Blankson J.N., Ray S.C., Wheelan S.J., Thomas D.L., Balagopal A.; RT "CMPK2 and BCL-G are associated with type 1 interferon-induced HIV RT restriction in humans."; RL Sci. Adv. 4:eaat0843-eaat0843(2018). RN [7] RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=34142025; DOI=10.1016/j.isci.2021.102498; RA Lai J.H., Wu D.W., Wu C.H., Hung L.F., Huang C.Y., Ka S.M., Chen A., RA Chang Z.F., Ho L.J.; RT "Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities RT through IFN-dependent and IFN-independent pathways."; RL IScience 24:102498-102498(2021). RN [8] RP FUNCTION. RX PubMed=36930652; DOI=10.1371/journal.pbio.3002039; RA Zhu M., Lv J., Wang W., Guo R., Zhong C., Antia A., Zeng Q., Li J., Liu Q., RA Zhou J., Zhu X., Fan B., Ding S., Li B.; RT "CMPK2 is a host restriction factor that inhibits infection of multiple RT coronaviruses in a cell-intrinsic manner."; RL PLoS Biol. 21:e3002039-e3002039(2023). RN [9] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=37075076; DOI=10.1371/journal.ppat.1011286; RA Pawlak J.B., Hsu J.C., Xia H., Han P., Suh H.W., Grove T.L., Morrison J., RA Shi P.Y., Cresswell P., Laurent-Rolle M.; RT "CMPK2 restricts Zika virus replication by inhibiting viral translation."; RL PLoS Pathog. 19:e1011286-e1011286(2023). CC -!- FUNCTION: Mitochondrial nucleotide monophosphate kinase needed for CC salvage dNTP synthesis that mediates immunomodulatory and antiviral CC activities through IFN-dependent and IFN-independent pathways CC (PubMed:17999954, PubMed:30083606, PubMed:36930652, PubMed:37075076). CC Restricts the replication of multiple viruses including flaviviruses or CC coronaviruses (PubMed:30083606, PubMed:36930652, PubMed:37075076). CC Together with viperin/RSAD2 and ddhCTP, suppresses the replication of CC several coronaviruses through inhibition of the viral RNA-dependent RNA CC polymerase activities (PubMed:36930652). Concerning flaviviruses, CC restricts RNA translation when localized to the mitochondria CC independently of its kinase activity (PubMed:37075076). Is able to CC phosphorylate dUMP, dCMP, CMP, UMP and monophosphates of the pyrimidine CC nucleoside analogs ddC, dFdC, araC, BVDU and FdUrd with ATP as CC phosphate donor. Efficacy is highest for dUMP followed by dCMP while CC CMP and UMP are poor substrates. Controls therefore mitochondrial DNA CC synthesis by supplying required deoxyribonucleotides (By similarity). CC CMPK2-dependent mitochondrial DNA synthesis is necessary for the CC production of oxidized mitochondrial DNA fragments after exposure to CC NLRP3 activators (By similarity). In turn, cytosolic oxidized mtDNA CC associates with the NLRP3 inflammasome complex and is required for its CC activation (By similarity). {ECO:0000250|UniProtKB:Q3U5Q7, CC ECO:0000269|PubMed:17999954, ECO:0000269|PubMed:23416111, CC ECO:0000269|PubMed:30083606, ECO:0000269|PubMed:34142025, CC ECO:0000269|PubMed:36930652, ECO:0000269|PubMed:37075076}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + CMP = ADP + CDP; Xref=Rhea:RHEA:11600, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:58069, ChEBI:CHEBI:60377, CC ChEBI:CHEBI:456216; EC=2.7.4.14; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + dCMP = ADP + dCDP; Xref=Rhea:RHEA:25094, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:57566, ChEBI:CHEBI:58593, CC ChEBI:CHEBI:456216; EC=2.7.4.14; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 2'-deoxyribonucleoside 5'-diphosphate + ATP = a 2'- CC deoxyribonucleoside 5'-triphosphate + ADP; Xref=Rhea:RHEA:44640, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61560, ChEBI:CHEBI:73316, CC ChEBI:CHEBI:456216; EC=2.7.4.6; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a ribonucleoside 5'-diphosphate + ATP = a ribonucleoside 5'- CC triphosphate + ADP; Xref=Rhea:RHEA:18113, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:57930, ChEBI:CHEBI:61557, ChEBI:CHEBI:456216; EC=2.7.4.6; CC Evidence={ECO:0000269|PubMed:23416111}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=3.09 mM for CMP; CC KM=6.3 mM for UMP; CC KM=1.31 mM for dCMP; CC KM=0.1 mM for dUMP; CC Vmax=1.64 umol/min/mg enzyme towards CMP; CC Vmax=0.19 umol/min/mg enzyme towards UMP; CC Vmax=1.77 umol/min/mg enzyme towards dCMP; CC Vmax=0.48 umol/min/mg enzyme towards dUMP; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:17999954, CC ECO:0000269|PubMed:34142025, ECO:0000269|PubMed:37075076}. CC Note=Mitochondrial localization is required for its antiviral function. CC {ECO:0000269|PubMed:37075076}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q5EBM0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q5EBM0-2; Sequence=VSP_033238, VSP_033239; CC Name=3; CC IsoId=Q5EBM0-3; Sequence=VSP_033240; CC Name=4; CC IsoId=Q5EBM0-4; Sequence=VSP_033241; CC -!- TISSUE SPECIFICITY: High levels are observed in myeloid, lymphoid and CC mesenchymal tissues. {ECO:0000269|PubMed:34142025}. CC -!- INDUCTION: By interferon-alpha (PubMed:30083606). IRF1 is crucial for CC the transcriptional activation of CMPK2 (PubMed:36930652). CC {ECO:0000269|PubMed:30083606, ECO:0000269|PubMed:36930652}. CC -!- SIMILARITY: Belongs to the thymidylate kinase family. {ECO:0000305}. 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; AK127983; BAC87217.1; -; mRNA. DR EMBL; BC016969; AAH16969.1; -; mRNA. DR EMBL; BC141802; AAI41803.1; -; mRNA. DR EMBL; BC132821; AAI32822.1; -; mRNA. DR EMBL; BC089425; AAH89425.1; -; mRNA. DR EMBL; BC144202; AAI44203.1; -; mRNA. DR CCDS; CCDS42648.1; -. [Q5EBM0-1] DR CCDS; CCDS58695.1; -. [Q5EBM0-3] DR CCDS; CCDS58696.1; -. [Q5EBM0-4] DR RefSeq; NP_001243406.1; NM_001256477.1. [Q5EBM0-4] DR RefSeq; NP_001243407.1; NM_001256478.1. [Q5EBM0-3] DR RefSeq; NP_997198.2; NM_207315.3. [Q5EBM0-1] DR AlphaFoldDB; Q5EBM0; -. DR SMR; Q5EBM0; -. DR STRING; 9606.ENSP00000256722; -. DR iPTMnet; Q5EBM0; -. DR PhosphoSitePlus; Q5EBM0; -. DR BioMuta; CMPK2; -. DR DMDM; 296439392; -. DR EPD; Q5EBM0; -. DR jPOST; Q5EBM0; -. DR MassIVE; Q5EBM0; -. DR MaxQB; Q5EBM0; -. DR PaxDb; 9606-ENSP00000256722; -. DR PeptideAtlas; Q5EBM0; -. DR ProteomicsDB; 62766; -. [Q5EBM0-1] DR ProteomicsDB; 62767; -. [Q5EBM0-2] DR ProteomicsDB; 62768; -. [Q5EBM0-3] DR ProteomicsDB; 62769; -. [Q5EBM0-4] DR Pumba; Q5EBM0; -. DR Antibodypedia; 26409; 91 antibodies from 22 providers. DR DNASU; 129607; -. DR Ensembl; ENST00000256722.10; ENSP00000256722.5; ENSG00000134326.12. [Q5EBM0-1] DR Ensembl; ENST00000404168.1; ENSP00000384915.1; ENSG00000134326.12. [Q5EBM0-4] DR Ensembl; ENST00000458098.5; ENSP00000396385.1; ENSG00000134326.12. [Q5EBM0-3] DR GeneID; 129607; -. DR KEGG; hsa:129607; -. DR MANE-Select; ENST00000256722.10; ENSP00000256722.5; NM_207315.4; NP_997198.2. DR UCSC; uc002qyo.5; human. [Q5EBM0-1] DR AGR; HGNC:27015; -. DR CTD; 129607; -. DR DisGeNET; 129607; -. DR GeneCards; CMPK2; -. DR HGNC; HGNC:27015; CMPK2. DR HPA; ENSG00000134326; Tissue enhanced (salivary). DR MIM; 611787; gene. DR neXtProt; NX_Q5EBM0; -. DR OpenTargets; ENSG00000134326; -. DR PharmGKB; PA162382556; -. DR VEuPathDB; HostDB:ENSG00000134326; -. DR eggNOG; KOG3327; Eukaryota. DR GeneTree; ENSGT00940000154030; -. DR HOGENOM; CLU_049896_0_0_1; -. DR InParanoid; Q5EBM0; -. DR OMA; ECTSLIP; -. DR OrthoDB; 168156at2759; -. DR PhylomeDB; Q5EBM0; -. DR TreeFam; TF328875; -. DR BRENDA; 2.7.4.14; 2681. DR PathwayCommons; Q5EBM0; -. DR SABIO-RK; Q5EBM0; -. DR BioGRID-ORCS; 129607; 17 hits in 1161 CRISPR screens. DR GenomeRNAi; 129607; -. DR Pharos; Q5EBM0; Tbio. DR PRO; PR:Q5EBM0; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q5EBM0; Protein. DR Bgee; ENSG00000134326; Expressed in palpebral conjunctiva and 184 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0036430; F:CMP kinase activity; IEA:RHEA. DR GO; GO:0004127; F:cytidylate kinase activity; IDA:MGI. DR GO; GO:0036431; F:dCMP kinase activity; IEA:RHEA. DR GO; GO:0004550; F:nucleoside diphosphate kinase activity; IDA:UniProtKB. DR GO; GO:0004798; F:thymidylate kinase activity; IBA:GO_Central. DR GO; GO:0033862; F:UMP kinase activity; IDA:MGI. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0006233; P:dTDP biosynthetic process; IBA:GO_Central. 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 Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR039430; Thymidylate_kin-like_dom. DR InterPro; IPR014505; UMP-CMP_kinase_2. DR PANTHER; PTHR10344; THYMIDYLATE KINASE; 1. DR PANTHER; PTHR10344:SF5; UMP-CMP KINASE 2, MITOCHONDRIAL; 1. DR Pfam; PF02223; Thymidylate_kin; 1. DR PIRSF; PIRSF019736; dTMP_TKRP1; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR Genevisible; Q5EBM0; HS. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Coiled coil; Kinase; Mitochondrion; KW Nucleotide-binding; Pyrimidine biosynthesis; Reference proteome; KW Transferase; Transit peptide. FT TRANSIT 1..98 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 99..449 FT /note="UMP-CMP kinase 2, mitochondrial" FT /id="PRO_0000331524" FT COILED 380..412 FT /evidence="ECO:0000255" FT BINDING 259..266 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255" FT VAR_SEQ 280..303 FT /note="LLKSPPSCIGQWRKIFDDEPTIIR -> PQPITLCTSGQRTCSNLTLSCCSL FT (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_033238" FT VAR_SEQ 304..449 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_033239" FT VAR_SEQ 332..449 FT /note="YWHSTATYAIATEVSGGLQHLPPAHHPVYQWPEDLLKPDLILLLTVSPEERL FT QRLQGRGMEKTREEAELEANSVFRQKVEMSYQRMENPGCHVVDASPSREKVLQTVLSLI FT QNSFSEP -> SQLGGTLYHPSLHLLGSEVCGTGILDSSHSSQGLE (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_033240" FT VAR_SEQ 410..449 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_033241" FT VARIANT 433 FT /note="K -> R (in dbSNP:rs6712141)" FT /id="VAR_055997" FT CONFLICT 448 FT /note="E -> G (in Ref. 3; AAH89425)" FT /evidence="ECO:0000305" SQ SEQUENCE 449 AA; 49448 MW; 99F382E34332B6DE CRC64; MAFARRLLRG PLSGPLLGRR GVCAGAMAPP RRFVLELPDC TLAHFALGAD APGDADAPDP RLAALLGPPE RSYSLCVPVT PDAGCGARVR AARLHQRLLH QLRRGPFQRC QLLRLLCYCP GGQAGGAQQG FLLRDPLDDP DTRQALLELL GACQEAPRPH LGEFEADPRG QLWQRLWEVQ DGRRLQVGCA QVVPVPEPPL HPVVPDLPSS VVFPDREAAR AVLEECTSFI PEARAVLDLV DQCPKQIQKG KFQVVAIEGL DATGKTTVTQ SVADSLKAVL LKSPPSCIGQ WRKIFDDEPT IIRRAFYSLG NYIVASEIAK ESAKSPVIVD RYWHSTATYA IATEVSGGLQ HLPPAHHPVY QWPEDLLKPD LILLLTVSPE ERLQRLQGRG MEKTREEAEL EANSVFRQKV EMSYQRMENP GCHVVDASPS REKVLQTVLS LIQNSFSEP //