Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNI8HAH)

• DOT Name: Diacylglycerol kinase delta (DGKD)
• Synonyms: DAG kinase delta; EC 2.7.1.107; 130 kDa diacylglycerol kinase; Diglyceride kinase delta; DGK-delta
• Gene Name: DGKD
• Related Disease:
  Advanced cancer
  LennoxGastaut syndrome
  Obsessive compulsive disorder
  Open-angle glaucoma
  Non-insulin dependent diabetes
  Hyperglycemia
• UniProt ID: DGKD_HUMAN
• PDB ID: 1R79; 3BQ7
• EC Number: 2.7.1.107
• Pfam ID: PF00130 ; PF00609 ; PF00781 ; PF00169 ; PF07647
• Sequence:
  MAAAAGAPPPGPPQPPPPPPPEESSDSEPEAEPGSPQKLIRKVSTSGQIRQKTIIKEGML
  TKQNNSFQRSKRRYFKLRGRTLYYAKTAKSIIFDEVDLTDASVAESSTKNVNNSFTVITP
  CRKLILCADNRKEMEDWIAALKTVQNREHFEPTQYSMDHFSGMHNWYACSHARPTYCNVC
  REALSGVTSHGLSCEVCKFKAHKRCAVRATNNCKWTTLASIGKDIIEDADGIAMPHQWLE
  GNLPVSAKCTVCDKTCGSVLRLQDWRCLWCKAMVHTSCKESLLTKCPLGLCKVSVIPPTA
  LNSIDSDGFWKASCPPSCTSPLLVFVNSKSGDNQGVKFLRRFKQLLNPAQVFDLMNGGPH
  LGLRLFQKFDTFRILVCGGDGSVGWVLSEIDSLNLHKQCQLGVLPLGTGNDLARVLGWGS
  ACDDDTQLPQILEKLERASTKMLDRWSVMAYEAKLPRQASSSTVTEDFSEDSEVQQILFY
  EDSVAAHLSKILTSDQHSVVISSAKVLCETVKDFVARVGKAYEKTTESSEESEVMAKKCS
  VLKEKLDSLLKTLDDESQASSSLPNPPPTIAEEAEDGDGSGSICGSTGDRLVASACPARP
  QIFRPREQLMLRANSLKKAIRQIIEHTEKAVDEQNAQTQEQEGFVLGLSESEEKMDHRVC
  PPLSHSESFGVPKGRSQRKVSKSPCEKLISKGSLSLGSSASLPPQPGSRDGLPALNTKIL
  YPNVRAGMSGSLPGGSVISRLLINADPFNSEPETLEYYTEKCVMNNYFGIGLDAKISLDF
  NNKRDEHPEKCRSRTKNMMWYGVLGTKELLHRTYKNLEQKVLLECDGRPIPLPSLQGIAV
  LNIPSYAGGTNFWGGTKEDDTFAAPSFDDKILEVVAVFGSMQMAVSRVIRLQHHRIAQCR
  TVKISILGDEGVPVQVDGEAWVQPPGYIRIVHKNRAQTLTRDRAFESTLKSWEDKQKCEL
  PRPPSCSLHPEMLSEEEATQMDQFGQAAGVLIHSIREIAQSHRDMEQELAHAVNASSKSM
  DRVYGKPRTTEGLNCSFVLEMVNNFRALRSETELLLSGKMALQLDPPQKEQLGSALAEMD
  RQLRRLADTPWLCQSAEPGDEESVMLDLAKRSRSGKFRLVTKFKKEKNNKNKEAHSSLGA
  PVHLWGTEEVAAWLEHLSLCEYKDIFTRHDIRGSELLHLERRDLKDLGVTKVGHMKRILC
  GIKELSRSAPAVEA
• 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). By controlling the levels of diacylglycerol, regulates for instance the PKC and EGF receptor signaling pathways and plays a crucial role during development. May also regulate clathrin-dependent endocytosis.
• Tissue Specificity: .Widely expressed.; [Isoform 1]: Only detected in ovary, and to a lesser extent in spleen.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
LennoxGastaut syndrome	DISOTGO5	Strong	Biomarker	[2]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[3]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[4]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Genetic Variation	[5]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[6]

7 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 delta (DGKD).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diacylglycerol kinase delta (DGKD).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Diacylglycerol kinase delta (DGKD).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Diacylglycerol kinase delta (DGKD).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Diacylglycerol kinase delta (DGKD).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Diacylglycerol kinase delta (DGKD).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Diacylglycerol kinase delta (DGKD).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Diacylglycerol kinase delta (DGKD).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Diacylglycerol kinase delta (DGKD).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose affects the localization of Diacylglycerol kinase delta (DGKD).	[16]

References

• [1] Diacylglycerol kinase modulates Akt phosphorylation through pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2).J Biol Chem. 2013 Jan 18;288(3):1439-47. doi: 10.1074/jbc.M112.407379. Epub 2012 Nov 26.
• [2] Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice.Am J Hum Genet. 2007 Apr;80(4):792-9. doi: 10.1086/513019. Epub 2007 Feb 12.
• [3] Abnormalities of the serotonergic system in diacylglycerol kinase -deficient mouse brain.Biochem Biophys Res Commun. 2018 Mar 18;497(4):1031-1037. doi: 10.1016/j.bbrc.2018.02.165. Epub 2018 Feb 24.
• [4] A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
• [5] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [6] Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance.Cell. 2008 Feb 8;132(3):375-86. doi: 10.1016/j.cell.2007.12.035.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] 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.
• [12] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Diacylglycerol kinase 1 transiently translocates to the plasma membrane in response to high glucose. Biochim Biophys Acta. 2012 Dec;1823(12):2210-6. doi: 10.1016/j.bbamcr.2012.08.019. Epub 2012 Sep 5.