Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYNPJ4B)

• DOT Name: Diacylglycerol kinase eta (DGKH)
• Synonyms: DAG kinase eta; EC 2.7.1.107; Diglyceride kinase eta; DGK-eta
• Gene Name: DGKH
• Related Disease:
  Mood disorder
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Bronchopulmonary dysplasia
  Mental disorder
  Panic disorder
  Asthma
  Lung cancer
  Lung carcinoma
  Urolithiasis
  Diabetic kidney disease
  Neoplasm of esophagus
• UniProt ID: DGKH_HUMAN
• EC Number: 2.7.1.107
• Pfam ID: PF00130 ; PF00609 ; PF00781 ; PF00169 ; PF07647
• Sequence:
  MAGAGGQHHPPGAAGGAAAGAGAAVTSAAASAGPGEDSSDSEAEQEGPQKLIRKVSTSGQ
  IRTKTSIKEGQLLKQTSSFQRWKKRYFKLRGRTLYYAKDSKSLIFDEVDLSDASVAEAST
  KNANNSFTIITPFRRLMLCAENRKEMEDWISSLKSVQTREPYEVAQFNVEHFSGMHNWYA
  CSHARPTFCNVCRESLSGVTSHGLSCEVCKFKAHKRCAVRATNNCKWTTLASIGKDIIED
  EDGVAMPHQWLEGNLPVSAKCAVCDKTCGSVLRLQDWKCLWCKTMVHTACKDLYHPICPL
  GQCKVSIIPPIALNSTDSDGFCRATFSFCVSPLLVFVNSKSGDNQGVKFLRRFKQLLNPA
  QVFDLMNGGPHLGLRLFQKFDNFRILVCGGDGSVGWVLSEIDKLNLNKQCQLGVLPLGTG
  NDLARVLGWGGSYDDDTQLPQILEKLERASTKMLDRWSIMTYELKLPPKASLLPGPPEAS
  EEFYMTIYEDSVATHLTKILNSDEHAVVISSAKTLCETVKDFVAKVEKTYDKTLENAVVA
  DAVASKCSVLNEKLEQLLQALHTDSQAAPVLPGLSPLIVEEDAVESSSEESLGESKEQLG
  DDVTKPSSQKAVKPREIMLRANSLKKAVRQVIEEAGKVMDDPTVHPCEPANQSSDYDSTE
  TDESKEEAKDDGAKESITVKTAPRSPDARASYGHSQTDSVPGPAVAASKENLPVLNTRII
  CPGLRAGLAASIAGSSIINKMLLANIDPFGATPFIDPDLDSVDGYSEKCVMNNYFGIGLD
  AKISLEFNNKREEHPEKCRSRTKNLMWYGVLGTRELLQRSYKNLEQRVQLECDGQYIPLP
  SLQGIAVLNIPSYAGGTNFWGGTKEDDIFAAPSFDDKILEVVAIFDSMQMAVSRVIKLQH
  HRIAQCRTVKITIFGDEGVPVQVDGEAWVQPPGIIKIVHKNRAQMLTRDRAFESTLKSWE
  DKQKCDSGKPVLRTHLYIHHAIDLATEEVSQMQLCSQAAEELITRICDAATIHCLLEQEL
  AHAVNACSHALNKANPRCPESLTRDTATEIAINVKALYNETESLLVGRVPLQLESPHEER
  VSNALHSVEVELQKLTEIPWLYYILHPNEDEEPPMDCTKRNNRSTVFRIVPKFKKEKVQK
  QKTSSQPVQKWGTEEVAAWLDLLNLGEYKDIFIRHDIRGAELLHLERRDLKDLGIPKVGH
  VKRILQGIKELGRSTPQSEV
• 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). Plays a key role in promoting cell growth. Activates the Ras/B-Raf/C-Raf/MEK/ERK signaling pathway induced by EGF. Regulates the recruitment of RAF1 and BRAF from cytoplasm to membranes and their heterodimerization.
• Tissue Specificity: .Expressed only in testis, kidney and colon.; [Isoform 2]: Ubiquitously expressed.
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mood disorder	DISLVMWO	Definitive	Biomarker	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[3]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[2]
Mental disorder	DIS3J5R8	Strong	Biomarker	[4]
Panic disorder	DISD3VNY	Strong	Biomarker	[4]
Asthma	DISW9QNS	moderate	Genetic Variation	[5]
Lung cancer	DISCM4YA	moderate	Biomarker	[6]
Lung carcinoma	DISTR26C	moderate	Biomarker	[6]
Urolithiasis	DISNFTKT	moderate	Genetic Variation	[7]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[8]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Diacylglycerol kinase eta (DGKH).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Diacylglycerol kinase eta (DGKH).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diacylglycerol kinase eta (DGKH).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Diacylglycerol kinase eta (DGKH).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Diacylglycerol kinase eta (DGKH).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Diacylglycerol kinase eta (DGKH).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Diacylglycerol kinase eta (DGKH).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Diacylglycerol kinase eta (DGKH).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Diacylglycerol kinase eta (DGKH).	[17]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Diacylglycerol kinase eta (DGKH).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Diacylglycerol kinase eta (DGKH).	[19]

References

• [1] Mania- and anxiety-like behavior and impaired maternal care in female diacylglycerol kinase eta and iota double knockout mice.Genes Brain Behav. 2020 Mar;19(3):e12570. doi: 10.1111/gbb.12570. Epub 2019 Apr 29.
• [2] Expressional profile of the diacylglycerol kinase eta gene DGKH.Eur Arch Psychiatry Clin Neurosci. 2017 Aug;267(5):445-454. doi: 10.1007/s00406-016-0695-4. Epub 2016 Apr 16.
• [3] The role of pre-, peri-, and postnatal risk factors in bipolar disorder and adult ADHD.J Neural Transm (Vienna). 2019 Sep;126(9):1117-1126. doi: 10.1007/s00702-019-01983-4. Epub 2019 Feb 13.
• [4] Whole-exome sequencing implicates DGKH as a risk gene for panic disorder in the Faroese population.Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1013-1022. doi: 10.1002/ajmg.b.32464. Epub 2016 Jun 3.
• [5] Genome-wide interrogation of longitudinal FEV1 in children with asthma.Am J Respir Crit Care Med. 2014 Sep 15;190(6):619-27. doi: 10.1164/rccm.201403-0460OC.
• [6] Diacylglycerol kinase modulates oncogenic properties of lung cancer cells.Clin Transl Oncol. 2014 Jan;16(1):29-35. doi: 10.1007/s12094-013-1036-y. Epub 2013 Apr 10.
• [7] Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.J Am Soc Nephrol. 2019 May;30(5):855-864. doi: 10.1681/ASN.2018090942. Epub 2019 Apr 11.
• [8] Hepatic expression profiling shows involvement of PKC epsilon, DGK eta, Tnfaip, and Rho kinase in type 2 diabetic nephropathy rats.J Cell Biochem. 2010 Nov 1;111(4):944-54. doi: 10.1002/jcb.22783.
• [9] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] 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.
• [18] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [19] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.