Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW8HLZC)

• DOT Name: Deoxycytidine kinase (DCK)
• Synonyms: dCK; EC 2.7.1.74; Deoxyadenosine kinase; EC 2.7.1.76; Deoxyguanosine kinase; EC 2.7.1.113
• Gene Name: DCK
• UniProt ID: DCK_HUMAN
• PDB ID: 1P5Z ; 1P60 ; 1P61 ; 1P62 ; 2A2Z ; 2A30 ; 2A7Q ; 2NO0 ; 2NO1 ; 2NO6 ; 2NO7 ; 2NO9 ; 2NOA ; 2QRN ; 2QRO ; 2ZI3 ; 2ZI4 ; 2ZI5 ; 2ZI6 ; 2ZI7 ; 2ZI9 ; 2ZIA ; 3HP1 ; 3IPX ; 3IPY ; 3KFX ; 3MJR ; 3QEJ ; 3QEN ; 3QEO ; 4JLJ ; 4JLK ; 4JLM ; 4JLN ; 4KCG ; 4L5B ; 4Q18 ; 4Q19 ; 4Q1A ; 4Q1B ; 4Q1C ; 4Q1D ; 4Q1E ; 4Q1F ; 5MQJ ; 5MQL ; 5MQT ; 7ZI1 ; 7ZI2 ; 7ZI3 ; 7ZI5 ; 7ZI6 ; 7ZI7 ; 7ZI8 ; 7ZI9 ; 7ZIA ; 7ZIB
• EC Number: 2.7.1.113; 2.7.1.74; 2.7.1.76
• Pfam ID: PF01712
• Sequence:
  MATPPKRSCPSFSASSEGTRIKKISIEGNIAAGKSTFVNILKQLCEDWEVVPEPVARWCN
  VQSTQDEFEELTMSQKNGGNVLQMMYEKPERWSFTFQTYACLSRIRAQLASLNGKLKDAE
  KPVLFFERSVYSDRYIFASNLYESECMNETEWTIYQDWHDWMNNQFGQSLELDGIIYLQA
  TPETCLHRIYLRGRNEEQGIPLEYLEKLHYKHESWLLHRTLKTNFDYLQEVPILTLDVNE
  DFKDKYESLVEKVKEFLSTL
• Function: Phosphorylates the deoxyribonucleosides deoxycytidine, deoxyguanosine and deoxyadenosine. Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Purine salvage (R-HSA-74217)
  Pyrimidine salvage (R-HSA-73614)
• BioCyc Pathway: MetaCyc:HS08100-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cytarabine	DMZD5QR	Approved	Deoxycytidine kinase (DCK) decreases the response to substance of Cytarabine.	[16]
Zalcitabine	DMH7MUV	Approved	Deoxycytidine kinase (DCK) affects the response to substance of Zalcitabine.	[17]

13 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 Deoxycytidine kinase (DCK).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Deoxycytidine kinase (DCK).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Deoxycytidine kinase (DCK).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Deoxycytidine kinase (DCK).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Deoxycytidine kinase (DCK).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Deoxycytidine kinase (DCK).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Deoxycytidine kinase (DCK).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Deoxycytidine kinase (DCK).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Deoxycytidine kinase (DCK).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Deoxycytidine kinase (DCK).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Deoxycytidine kinase (DCK).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Deoxycytidine kinase (DCK).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Deoxycytidine kinase (DCK).	[15]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Emtricitabine	DMBMUWZ	Approved	Emtricitabine affects the binding of Deoxycytidine kinase (DCK).	[10]
DEOXYCYTIDINE	DMYE5LJ	Approved	DEOXYCYTIDINE affects the binding of Deoxycytidine kinase (DCK).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Deoxycytidine kinase (DCK).	[12]

References

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• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [10] Nonenantioselectivity property of human deoxycytidine kinase explained by structures of the enzyme in complex with L- and D-nucleosides. J Med Chem. 2007 Jun 28;50(13):3004-14. doi: 10.1021/jm0700215. Epub 2007 May 27.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells. Cancer Res. 2008 Apr 1;68(7):2349-57. doi: 10.1158/0008-5472.CAN-07-5528.
• [17] Molecular basis of 2',3'-dideoxycytidine-induced drug resistance in human cells. Mol Cell Biochem. 2002 Feb;231(1-2):173-7. doi: 10.1023/a:1014441209108.