Details of Drug Off-Target (DOT)

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

• DOT Name: Diacylglycerol kinase alpha (DGKA)
• Synonyms: DAG kinase alpha; EC 2.7.1.107; EC 2.7.1.93; 80 kDa diacylglycerol kinase; Diglyceride kinase alpha; DGK-alpha
• Gene Name: DGKA
• UniProt ID: DGKA_HUMAN
• PDB ID: 1TUZ; 6IIE
• EC Number: 2.7.1.107; 2.7.1.93
• Pfam ID: PF00130 ; PF14513 ; PF00609 ; PF00781
• Sequence:
  MAKERGLISPSDFAQLQKYMEYSTKKVSDVLKLFEDGEMAKYVQGDAIGYEGFQQFLKIY
  LEVDNVPRHLSLALFQSFETGHCLNETNVTKDVVCLNDVSCYFSLLEGGRPEDKLEFTFK
  LYDTDRNGILDSSEVDKIILQMMRVAEYLDWDVSELRPILQEMMKEIDYDGSGSVSQAEW
  VRAGATTVPLLVLLGLEMTLKDDGQHMWRPKRFPRPVYCNLCESSIGLGKQGLSCNLCKY
  TVHDQCAMKALPCEVSTYAKSRKDIGVQSHVWVRGGCESGRCDRCQKKIRIYHSLTGLHC
  VWCHLEIHDDCLQAVGHECDCGLLRDHILPPSSIYPSVLASGPDRKNSKTSQKTMDDLNL
  STSEALRIDPVPNTHPLLVFVNPKSGGKQGQRVLWKFQYILNPRQVFNLLKDGPEIGLRL
  FKDVPDSRILVCGGDGTVGWILETIDKANLPVLPPVAVLPLGTGNDLARCLRWGGGYEGQ
  NLAKILKDLEMSKVVHMDRWSVEVIPQQTEEKSDPVPFQIINNYFSIGVDASIAHRFHIM
  REKYPEKFNSRMKNKLWYFEFATSESIFSTCKKLEESLTVEICGKPLDLSNLSLEGIAVL
  NIPSMHGGSNLWGDTRRPHGDIYGINQALGATAKVITDPDILKTCVPDLSDKRLEVVGLE
  GAIEMGQIYTKLKNAGRRLAKCSEITFHTTKTLPMQIDGEPWMQTPCTIKITHKNQMPML
  MGPPPRSTNFFGFLS
• 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. Also plays an important role in the biosynthesis of complex lipids (Probable). Can also phosphorylate 1-alkyl-2-acylglycerol in vitro as efficiently as diacylglycerol provided it contains an arachidonoyl group. Also involved in the production of alkyl-lysophosphatidic acid, another bioactive lipid, through the phosphorylation of 1-alkyl-2-acetyl glycerol.
• Tissue Specificity: Expressed in lymphocytes.
• 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

2 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 alpha (DGKA).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Diacylglycerol kinase alpha (DGKA).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Diacylglycerol kinase alpha (DGKA).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Diacylglycerol kinase alpha (DGKA).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Diacylglycerol kinase alpha (DGKA).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Diacylglycerol kinase alpha (DGKA).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Diacylglycerol kinase alpha (DGKA).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Diacylglycerol kinase alpha (DGKA).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Diacylglycerol kinase alpha (DGKA).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Diacylglycerol kinase alpha (DGKA).	[9]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Diacylglycerol kinase alpha (DGKA).	[2]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Diacylglycerol kinase alpha (DGKA).	[2]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Diacylglycerol kinase alpha (DGKA).	[2]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Diacylglycerol kinase alpha (DGKA).	[2]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Diacylglycerol kinase alpha (DGKA).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Diacylglycerol kinase alpha (DGKA).	[12]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [2] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [3] 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.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Unique signatures of stress-induced senescent human astrocytes. Exp Neurol. 2020 Dec;334:113466. doi: 10.1016/j.expneurol.2020.113466. Epub 2020 Sep 17.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] 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.
• [10] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [11] 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.
• [12] 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.