Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT78HUZB)

• DOT Name: Deoxyguanosine kinase, mitochondrial (DGUOK)
• Synonyms: EC 2.7.1.113; Deoxyadenosine kinase, mitochondrial; EC 2.7.1.76
• Gene Name: DGUOK
• Related Disease:
  Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
  Acute liver failure
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Childhood acute lymphoblastic leukemia
  Cholestasis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Cystathioninuria
  Hepatic encephalopathy
  Inflammatory bowel disease
  Liver cirrhosis
  Lung adenocarcinoma
  Mitochondrial disease
  Mitochondrial DNA depletion syndrome 4a
  Mitochondrial DNA depletion syndrome, hepatocerebral form
  Myopathy
  Neoplasm
  Portal hypertension, noncirrhotic
  Liver failure
  Melanoma
  Mitochondrial DNA depletion syndrome
  Progressive external ophthalmoplegia
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4
  Asthma
  Obsolete portal hypertension, noncirrhotic
• UniProt ID: DGUOK_HUMAN
• PDB ID: 2OCP
• EC Number: 2.7.1.113; 2.7.1.76
• Pfam ID: PF01712
• Sequence:
  MAAGRLFLSRLRAPFSSMAKSPLEGVSSSRGLHAGRGPRRLSIEGNIAVGKSTFVKLLTK
  TYPEWHVATEPVATWQNIQAAGTQKACTAQSLGNLLDMMYREPARWSYTFQTFSFLSRLK
  VQLEPFPEKLLQARKPVQIFERSVYSDRYIFAKNLFENGSLSDIEWHIYQDWHSFLLWEF
  ASRITLHGFIYLQASPQVCLKRLYQRAREEEKGIELAYLEQLHGQHEAWLIHKTTKLHFE
  ALMNIPVLVLDVNDDFSEEVTKQEDLMREVNTFVKNL
• Function: Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on DGUOK and TK2. Phosphorylates certain nucleoside analogs. Widely used as target of antiviral and chemotherapeutic agents.
• Tissue Specificity: Ubiquitous. Highest expression in muscle, brain, liver and lymphoid tissues.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway: Purine salvage (R-HSA-74217)
• BioCyc Pathway: MetaCyc:HS03819-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	DISKE17B	Definitive	Autosomal recessive	[1]
Acute liver failure	DIS5EZKX	Strong	Biomarker	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[3]
Cholestasis	DISDJJWE	Strong	Genetic Variation	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[7]
Cystathioninuria	DISOUZ3T	Strong	Genetic Variation	[8]
Hepatic encephalopathy	DISEAKAN	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[11]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[12]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[13]
Mitochondrial DNA depletion syndrome 4a	DISU4RVU	Strong	Genetic Variation	[14]
Mitochondrial DNA depletion syndrome, hepatocerebral form	DISXOJLH	Strong	Biomarker	[15]
Myopathy	DISOWG27	Strong	Genetic Variation	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Portal hypertension, noncirrhotic	DISZZMLV	Strong	Biomarker	[17]
Liver failure	DISLGEL6	moderate	Biomarker	[15]
Melanoma	DIS1RRCY	moderate	Altered Expression	[18]
Mitochondrial DNA depletion syndrome	DISIGZSM	moderate	Genetic Variation	[19]
Progressive external ophthalmoplegia	DISX4ATI	moderate	Genetic Variation	[20]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4	DISANCL5	Supportive	Autosomal recessive	[21]
Asthma	DISW9QNS	Disputed	Biomarker	[22]
Obsolete portal hypertension, noncirrhotic	DISC97P7	Limited	Autosomal recessive	[1]

6 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 Deoxyguanosine kinase, mitochondrial (DGUOK).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Deoxyguanosine kinase, mitochondrial (DGUOK).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Deoxyguanosine kinase, mitochondrial (DGUOK).	[25]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Deoxyguanosine kinase, mitochondrial (DGUOK).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Deoxyguanosine kinase, mitochondrial (DGUOK).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Deoxyguanosine kinase, mitochondrial (DGUOK).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Deoxyguanosine kinase, mitochondrial (DGUOK).	[28]

References

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• [2] Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism.PLoS One. 2016 Aug 2;11(8):e0156738. doi: 10.1371/journal.pone.0156738. eCollection 2016.
• [3] Real-time quantitative PCR assays for deoxycytidine kinase, deoxyguanosine kinase and 5'-nucleotidase mRNA measurement in cell lines and in patients with leukemia.Leukemia. 2002 Mar;16(3):386-92. doi: 10.1038/sj.leu.2402388.
• [4] Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer.Clin Cancer Res. 2015 Nov 15;21(22):5008-12. doi: 10.1158/1078-0432.CCR-15-0413. Epub 2015 Sep 29.
• [5] Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure.J Pediatr. 2014 Mar;164(3):553-9.e1-2. doi: 10.1016/j.jpeds.2013.10.082. Epub 2013 Dec 8.
• [6] Apoptotic Activity of Lactobacillus plantarum DGK-17-Fermented Soybean Seed Extract in Human Colon Cancer Cells via ROS-JNK Signaling Pathway.J Food Sci. 2017 Jun;82(6):1475-1483. doi: 10.1111/1750-3841.13732. Epub 2017 May 10.
• [7] Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer.Mol Carcinog. 2017 Jul;56(7):1743-1752. doi: 10.1002/mc.22631. Epub 2017 Mar 6.
• [8] Novel mutation in DGUOK in hepatocerebral mitochondrial DNA depletion syndrome associated with cystathioninuria.Am J Med Genet A. 2005 Jun 15;135(3):289-91. doi: 10.1002/ajmg.a.30748.
• [9] Deoxyguanosine kinase deficiency: a report of four patients.J Pediatr Endocrinol Metab. 2017 May 24;30(6):697-702. doi: 10.1515/jpem-2016-0268.
• [10] Clinical Course of Nodular Regenerative Hyperplasia in Thiopurine Treated Inflammatory Bowel Disease Patients.Clin Gastroenterol Hepatol. 2019 Feb;17(3):568-570. doi: 10.1016/j.cgh.2018.05.009. Epub 2018 Jun 1.
• [11] Hepato-cerebral syndrome: genetic and pathological studies in an infant with a dGK mutation.Acta Neuropathol. 2004 Aug;108(2):168-71. doi: 10.1007/s00401-004-0872-9. Epub 2004 May 19.
• [12] The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma.EMBO Mol Med. 2019 Dec;11(12):e10849. doi: 10.15252/emmm.201910849. Epub 2019 Oct 21.
• [13] Recessive deoxyguanosine kinase deficiency causes juvenile onset mitochondrial myopathy.Mol Genet Metab. 2012 Sep;107(1-2):92-4. doi: 10.1016/j.ymgme.2012.04.019. Epub 2012 Apr 26.
• [14] Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood.J Pediatr. 2007 May;150(5):531-4, 534.e1-6. doi: 10.1016/j.jpeds.2007.01.044.
• [15] A Screen Using iPSC-Derived Hepatocytes Reveals NAD(+) as a Potential Treatment for mtDNA Depletion Syndrome.Cell Rep. 2018 Nov 6;25(6):1469-1484.e5. doi: 10.1016/j.celrep.2018.10.036.
• [16] Depletion of the other genome-mitochondrial DNA depletion syndromes in humans.J Mol Med (Berl). 2002 Jul;80(7):389-96. doi: 10.1007/s00109-002-0343-5. Epub 2002 May 24.
• [17] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [18] Nucleoside Analog Activity in Malignant Melanoma Cell Lines.Nucleosides Nucleotides Nucleic Acids. 2015;34(9):639-49. doi: 10.1080/15257770.2015.1047029.
• [19] A fatal case of mitochondrial DNA depletion syndrome with novel compound heterozygous variants in the deoxyguanosine kinase gene.Oncotarget. 2017 Sep 15;8(48):84309-84319. doi: 10.18632/oncotarget.20905. eCollection 2017 Oct 13.
• [20] Alteration of nucleotide metabolism: a new mechanism for mitochondrial disorders.Clin Chem Lab Med. 2003 Jul;41(7):845-51. doi: 10.1515/CCLM.2003.128.
• [21] Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. Brain. 2012 Nov;135(Pt 11):3404-15. doi: 10.1093/brain/aws258. Epub 2012 Oct 4.
• [22] Diacylglycerol kinase promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms.Sci Signal. 2019 Sep 3;12(597):eaax3332. doi: 10.1126/scisignal.aax3332.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [25] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [26] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [27] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [28] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.