Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWS86AS)

• DOT Name: Diacylglycerol kinase epsilon (DGKE)
• Synonyms: DAG kinase epsilon; EC 2.7.1.107; Diglyceride kinase epsilon; DGK-epsilon
• Gene Name: DGKE
• Related Disease:
  Thrombotic microangiopathy
  Atypical hemolytic uremic syndrome
  Cardiac disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epilepsy
  Hemolytic-uremic syndrome
  Huntington disease
  Hypoalbuminemia
  Immunoglobulin-mediated membranoproliferative glomerulonephritis
  Kidney failure
  Liver cirrhosis
  Mitochondrial DNA depletion syndrome
  Non-immunoglobulin-mediated membranoproliferative glomerulonephritis
  Obesity
  Retinitis pigmentosa
  Atypical hemolytic-uremic syndrome with DGKE deficiency
  Asthma
  Thrombotic thrombocytopenic purpura
  Advanced cancer
  Nephrotic syndrome
• UniProt ID: DGKE_HUMAN
• EC Number: 2.7.1.107
• Pfam ID: PF00130 ; PF00609 ; PF00781
• Sequence:
  MEAERRPAPGSPSEGLFADGHLILWTLCSVLLPVFITFWCSLQRSRRQLHRRDIFRKSKH
  GWRDTDLFSQPTYCCVCAQHILQGAFCDCCGLRVDEGCLRKADKRFQCKEIMLKNDTKVL
  DAMPHHWIRGNVPLCSYCMVCKQQCGCQPKLCDYRCIWCQKTVHDECMKNSLKNEKCDFG
  EFKNLIIPPSYLTSINQMRKDKKTDYEVLASKLGKQWTPLIILANSRSGTNMGEGLLGEF
  RILLNPVQVFDVTKTPPIKALQLCTLLPYYSARVLVCGGDGTVGWVLDAVDDMKIKGQEK
  YIPQVAVLPLGTGNDLSNTLGWGTGYAGEIPVAQVLRNVMEADGIKLDRWKVQVTNKGYY
  NLRKPKEFTMNNYFSVGPDALMALNFHAHREKAPSLFSSRILNKAVYLFYGTKDCLVQEC
  KDLNKKVELELDGERVALPSLEGIIVLNIGYWGGGCRLWEGMGDETYPLARHDDGLLEVV
  GVYGSFHCAQIQVKLANPFRIGQAHTVRLILKCSMMPMQVDGEPWAQGPCTVTITHKTHA
  MMLYFSGEQTDDDISSTSDQEDIKATE
• Function: Membrane-bound 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. Also plays an important role in the biosynthesis of complex lipids. Displays specificity for diacylglycerol substrates with an arachidonoyl acyl chain at the sn-2 position, with the highest activity toward 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol the main diacylglycerol intermediate within the phosphatidylinositol turnover cycle. Can also phosphorylate diacylglycerol substrates with a linoleoyl acyl chain at the sn-2 position but much less efficiently.
• Tissue Specificity: Expressed predominantly in testis. Expressed in endothelium, platelets and podocytes (at protein level).
• 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

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thrombotic microangiopathy	DISLZ0VW	Definitive	Genetic Variation	[1]
Atypical hemolytic uremic syndrome	DIS6FUDJ	Strong	Biomarker	[2]
Cardiac disease	DISVO1I5	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[5]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Hemolytic-uremic syndrome	DISSCBGW	Strong	Genetic Variation	[6]
Huntington disease	DISQPLA4	Strong	Altered Expression	[7]
Hypoalbuminemia	DISJEW1H	Strong	Altered Expression	[8]
Immunoglobulin-mediated membranoproliferative glomerulonephritis	DISNHRNG	Strong	Autosomal recessive	[9]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[10]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[11]
Mitochondrial DNA depletion syndrome	DISIGZSM	Strong	Genetic Variation	[12]
Non-immunoglobulin-mediated membranoproliferative glomerulonephritis	DISLMV1J	Strong	Biomarker	[13]
Obesity	DIS47Y1K	Strong	Genetic Variation	[14]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[15]
Atypical hemolytic-uremic syndrome with DGKE deficiency	DIS17ALE	Supportive	Autosomal recessive	[16]
Asthma	DISW9QNS	Disputed	Biomarker	[17]
Thrombotic thrombocytopenic purpura	DIS3LDOU	Disputed	Genetic Variation	[18]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[19]
Nephrotic syndrome	DISSPSC2	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Diacylglycerol kinase epsilon (DGKE).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diacylglycerol kinase epsilon (DGKE).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Diacylglycerol kinase epsilon (DGKE).	[23]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Diacylglycerol kinase epsilon (DGKE).	[24]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Diacylglycerol kinase epsilon (DGKE).	[25]
Epanova	DMHEAGL	Approved	Epanova decreases the expression of Diacylglycerol kinase epsilon (DGKE).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Diacylglycerol kinase epsilon (DGKE).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Diacylglycerol kinase epsilon (DGKE).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diacylglycerol kinase epsilon (DGKE).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Diacylglycerol kinase epsilon (DGKE).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Diacylglycerol kinase epsilon (DGKE).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Diacylglycerol kinase epsilon (DGKE).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Diacylglycerol kinase epsilon (DGKE).	[32]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Diacylglycerol kinase epsilon (DGKE).	[33]

References

• [1] Diacylglycerol kinase epsilon nephropathy: late diagnosis and therapeutic implications.Clin Kidney J. 2019 May 14;12(5):641-644. doi: 10.1093/ckj/sfz043. eCollection 2019 Oct.
• [2] Whole-exome sequencing detects mutations in pediatric patients with atypical hemolytic uremic syndrome in Taiwan.Clin Chim Acta. 2019 Jul;494:143-150. doi: 10.1016/j.cca.2019.03.1623. Epub 2019 Mar 21.
• [3] Expression, Purification, and Properties of a Human Arachidonoyl-Specific Isoform of Diacylglycerol Kinase.Biochemistry. 2017 Mar 7;56(9):1337-1347. doi: 10.1021/acs.biochem.6b01193. Epub 2017 Feb 24.
• [4] 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.
• [5] 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.
• [6] Atypical presentation of atypical haemolytic uraemic syndrome.BMJ Case Rep. 2018 Feb 11;2018:bcr2017222560. doi: 10.1136/bcr-2017-222560.
• [7] Inhibition of lipid signaling enzyme diacylglycerol kinase epsilon attenuates mutant huntingtin toxicity.J Biol Chem. 2012 Jun 15;287(25):21204-13. doi: 10.1074/jbc.M111.321661. Epub 2012 Apr 16.
• [8] HUS and atypical HUS.Blood. 2017 May 25;129(21):2847-2856. doi: 10.1182/blood-2016-11-709865. Epub 2017 Apr 17.
• [9] DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol. 2013 Feb;24(3):377-84. doi: 10.1681/ASN.2012090903. Epub 2012 Dec 28.
• [10] Complement mutations in diacylglycerol kinase--associated atypical hemolytic uremic syndrome.Clin J Am Soc Nephrol. 2014 Sep 5;9(9):1611-9. doi: 10.2215/CJN.01640214. Epub 2014 Aug 18.
• [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] New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome.Arch Neurol. 2005 May;62(5):745-7. doi: 10.1001/archneur.62.5.745.
• [13] The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase .J Am Soc Nephrol. 2017 Oct;28(10):3066-3075. doi: 10.1681/ASN.2017010031. Epub 2017 May 19.
• [14] Deletion of diacylglycerol kinase confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes.FASEB J. 2018 Aug;32(8):4121-4131. doi: 10.1096/fj.201701050R. Epub 2018 Mar 6.
• [15] Characterization of the human diacylglycerol kinase epsilon gene and its assessment as a candidate for inherited retinitis pigmentosa.Gene. 1999 Oct 18;239(1):185-92. doi: 10.1016/s0378-1119(99)00345-5.
• [16] Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013 May;45(5):531-6. doi: 10.1038/ng.2590. Epub 2013 Mar 31.
• [17] 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.
• [18] Complement activation in diseases presenting with thrombotic microangiopathy.Eur J Intern Med. 2013 Sep;24(6):496-502. doi: 10.1016/j.ejim.2013.05.009. Epub 2013 Jun 4.
• [19] 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.
• [20] The expanding phenotypic spectra of kidney diseases: insights from genetic studies.Nat Rev Nephrol. 2016 Aug;12(8):472-83. doi: 10.1038/nrneph.2016.87. Epub 2016 Jul 4.
• [21] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [22] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [23] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [24] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [25] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [26] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [27] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [28] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [29] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [30] 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.
• [31] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [33] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.