Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOG90R0)

• DOT Name: UMP-CMP kinase 2, mitochondrial (CMPK2)
• Synonyms: EC 2.7.4.14; Nucleoside-diphosphate kinase; EC 2.7.4.6
• Gene Name: CMPK2
• Related Disease:
  Breast cancer
  Colorectal carcinoma
  Metastatic malignant neoplasm
  Neuroblastoma
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Gastric cancer
  Male infertility
  Melanoma
  Neoplasm
  Prostate carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Tuberculosis
  Colon cancer
  Colon carcinoma
  Acute lymphocytic leukaemia
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Glioma
  Lymphoid leukemia
• UniProt ID: CMPK2_HUMAN
• EC Number: 2.7.4.14; 2.7.4.6
• Pfam ID: PF02223
• Sequence:
  MAFARRLLRGPLSGPLLGRRGVCAGAMAPPRRFVLELPDCTLAHFALGADAPGDADAPDP
  RLAALLGPPERSYSLCVPVTPDAGCGARVRAARLHQRLLHQLRRGPFQRCQLLRLLCYCP
  GGQAGGAQQGFLLRDPLDDPDTRQALLELLGACQEAPRPHLGEFEADPRGQLWQRLWEVQ
  DGRRLQVGCAQVVPVPEPPLHPVVPDLPSSVVFPDREAARAVLEECTSFIPEARAVLDLV
  DQCPKQIQKGKFQVVAIEGLDATGKTTVTQSVADSLKAVLLKSPPSCIGQWRKIFDDEPT
  IIRRAFYSLGNYIVASEIAKESAKSPVIVDRYWHSTATYAIATEVSGGLQHLPPAHHPVY
  QWPEDLLKPDLILLLTVSPEERLQRLQGRGMEKTREEAELEANSVFRQKVEMSYQRMENP
  GCHVVDASPSREKVLQTVLSLIQNSFSEP
• Function: Mitochondrial nucleotide monophosphate kinase needed for salvage dNTP synthesis that mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways. Restricts the replication of multiple viruses including flaviviruses or coronaviruses. Together with viperin/RSAD2 and ddhCTP, suppresses the replication of several coronaviruses through inhibition of the viral RNA-dependent RNA polymerase activities. Concerning flaviviruses, restricts RNA translation when localized to the mitochondria independently of its kinase activity. Is able to phosphorylate dUMP, dCMP, CMP, UMP and monophosphates of the pyrimidine nucleoside analogs ddC, dFdC, araC, BVDU and FdUrd with ATP as phosphate donor. Efficacy is highest for dUMP followed by dCMP while CMP and UMP are poor substrates. Controls therefore mitochondrial DNA synthesis by supplying required deoxyribonucleotides. CMPK2-dependent mitochondrial DNA synthesis is necessary for the production of oxidized mitochondrial DNA fragments after exposure to NLRP3 activators. In turn, cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation.
• Tissue Specificity: High levels are observed in myeloid, lymphoid and mesenchymal tissues.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Biosynthesis of cofactors (hsa01240)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Definitive	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Male infertility	DISY3YZZ	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[9]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[10]
Colon cancer	DISVC52G	moderate	Altered Expression	[11]
Colon carcinoma	DISJYKUO	moderate	Altered Expression	[11]
Acute lymphocytic leukaemia	DISPX75S	Limited	Altered Expression	[12]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[13]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[14]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[14]
Cervical Intraepithelial neoplasia	DISXP757	Limited	Altered Expression	[14]
Glioma	DIS5RPEH	Limited	Biomarker	[15]
Lymphoid leukemia	DIS65TYQ	Limited	Altered Expression	[12]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[25]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[26]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[27]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[28]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[25]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[29]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[30]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of UMP-CMP kinase 2, mitochondrial (CMPK2).	[34]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of UMP-CMP kinase 2, mitochondrial (CMPK2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of UMP-CMP kinase 2, mitochondrial (CMPK2).	[32]

References

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• [15] Nucleoside diphosphate kinase beta (Nm23-R1/NDPKbeta) is associated with intermediate filaments and becomes upregulated upon cAMP-induced differentiation of rat C6 glioma.Exp Cell Res. 2000 Nov 25;261(1):127-38. doi: 10.1006/excr.2000.5037.
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