Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHIMF7L)

• DOT Name: Diacylglycerol kinase kappa (DGKK)
• Synonyms: DAG kinase kappa; DGK-kappa; EC 2.7.1.107; 142 kDa diacylglycerol kinase; Diglyceride kinase kappa
• Gene Name: DGKK
• Related Disease:
  Fragile X syndrome
  Hepatocellular carcinoma
  Hypospadias
  Prostate carcinoma
• UniProt ID: DGKK_HUMAN
• EC Number: 2.7.1.107
• Pfam ID: PF00130 ; PF00609 ; PF00781 ; PF00169
• Sequence:
  MDRGAAAAQGTAPPQDGEQPAESPEPPPPWPPPPPPPAPPPAPPLLSEASPEPIPEPCPE
  LAPGPCPEATSESATELYTEPTPEPATEPASEPAPEPATEPAPEPATEPAPEPAPEPATE
  SAPEPTPEPALESVPEPAPELTPEVAPELAPEPTPEPVTELAPEFCPEAAPEFRPSPAPC
  LLQCPVDTRERGLKTSPSPSPSPSPRTPMSWSRIKKILKEGPMLKNCNSFKRWKLRYFLV
  QGQKLYFAHHPAFAHFETIDLSQATVAESSCRNLCHSFCVITPQRKITLAAPNRKDMEEW
  INIIKTIQQGEIYKIPAAENNPFLVGMHCWYSSYSHRTQHCNVCRESIPALSRDAIICEV
  CKVKSHRLCALRASKDCKWNTLSITDDLLLPADEVNMPHQWVEGNMPVSSQCAVCHESCG
  SYQRLQDFRCLWCNSTVHDDCRRRFSKECCFRSHRSSVIPPTALSDPKGDGQLVVSSDFW
  NLDWSSACSCPLLIFINSKSGDHQGIVFLRKFKQYLNPSQVFDLLKGGPEAGLSMFKNFA
  RFRILVCGGDGSVSWVLSLIDAFGLHEKCQLAVIPLGTGNDLARVLGWGAFWNKSKSPLD
  ILNRVEQASVRILDRWSVMIRETPRQTPLLKGQVEMDVPRFEAAAIQHLESAATELNKIL
  KAKYPTEMIIATRFLCSAVEDFVVDIVKAWGQIKQNNTAIVSVILKSDLMYDRLSVLIDV
  LAEEAAATSAEKSATEYADSSKADRKPFIPQIDHIAKCKLELATKAQSLQKSLKLIIFQV
  EQALDEESRQTISVKNFSSTFFLEDDPEDINQTSPRRRSRRGTLSSISSLKSEDLDNLNL
  DHLHFTPESIRFKEKCVMNNYFGIGLDAKISLDFNTRRDEHPGQYNSRLKNKMWYGLLGT
  KELLQRSYRKLEERVHLECDGETISLPNLQGIVVLNITSYAGGINFWGSNTATTEYEAPA
  IDDGKLEVVAIFGSVQMAMSRIINLHHHRIAQCHEVMITIDGEEGIPVQVDGEAWIQRPG
  LIKIRYKNAAQMLTRDRDFENSMKMWEYKHTEIQAAPQPQLDFQDSQESLSDEEYAQMQH
  LARLAENLISKLNDLSKIHQHVSVLMGSVNASANILNDIFYGQDSGNEMGAASCIPIETL
  SRNDAVDVTFSLKGLYDDTTAFLDEKLLRSAEDETALQSALDAMNKEFKKLSEIDWMNPI
  FVPEEKSSDTDSRSLRLKIKFPKLGKKKVEEERKPKSGQSVQSFIGNLWHRRHREDEAEG
  DDPLTPSRSQL
• Function: Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids. Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (Probable).
• Tissue Specificity: Expressed in testis, and to a lesser extent in placenta.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Phospholipase D sig.ling pathway (hsa04072)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway: Effects of PIP2 hydrolysis (R-HSA-114508)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Hypospadias	DIS48CCP	Limited	Genetic Variation	[3]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Diacylglycerol kinase kappa (DGKK).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Diacylglycerol kinase kappa (DGKK).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Diacylglycerol kinase kappa (DGKK).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Diacylglycerol kinase kappa (DGKK).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Diacylglycerol kinase kappa (DGKK).	[10]

2 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 increases the methylation of Diacylglycerol kinase kappa (DGKK).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Diacylglycerol kinase kappa (DGKK).	[9]

References

• [1] Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3619-28. doi: 10.1073/pnas.1522631113. Epub 2016 May 27.
• [2] Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH(-)).Theranostics. 2019 Oct 18;9(26):8109-8126. doi: 10.7150/thno.35378. eCollection 2019.
• [3] Association between diacylglycerol kinase kappa variants and hypospadias susceptibility in a Han Chinese population.Asian J Androl. 2018 Jan-Feb;20(1):85-89. doi: 10.4103/aja.aja_13_17.
• [4] Genome-wide association study of prostate cancer-specific survival.Cancer Epidemiol Biomarkers Prev. 2015 Nov;24(11):1796-800. doi: 10.1158/1055-9965.EPI-15-0543. Epub 2015 Aug 25.
• [5] 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.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [9] 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.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.