Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTT9SZJ)

• DOT Name: Diacylglycerol kinase beta (DGKB)
• Synonyms: DAG kinase beta; EC 2.7.1.107; 90 kDa diacylglycerol kinase; Diglyceride kinase beta; DGK-beta
• Gene Name: DGKB
• Related Disease:
  Atrial fibrillation
  Bipolar disorder
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Depression
  Liver cirrhosis
  Mitochondrial DNA depletion syndrome
  Neoplasm
  Acute myelogenous leukaemia
  Familial atrial fibrillation
  Asthma
  Advanced cancer
  Non-insulin dependent diabetes
• UniProt ID: DGKB_HUMAN
• EC Number: 2.7.1.107
• Pfam ID: PF00130 ; PF14513 ; PF00609 ; PF00781 ; PF13499
• Sequence:
  MTNQEKWAHLSPSEFSQLQKYAEYSTKKLKDVLEEFHGNGVLAKYNPEGKQDILNQTIDF
  EGFKLFMKTFLEAELPDDFTAHLFMSFSNKFPHSSPMVKSKPALLSGGLRMNKGAITPPR
  TTSPANTCSPEVIHLKDIVCYLSLLERGRPEDKLEFMFRLYDTDGNGFLDSSELENIISQ
  MMHVAEYLEWDVTELNPILHEMMEEIDYDHDGTVSLEEWIQGGMTTIPLLVLLGLENNVK
  DDGQHVWRLKHFNKPAYCNLCLNMLIGVGKQGLCCSFCKYTVHERCVARAPPSCIKTYVK
  SKRNTDVMHHYWVEGNCPTKCDKCHKTVKCYQGLTGLHCVWCQITLHNKCASHLKPECDC
  GPLKDHILPPTTICPVVLQTLPTSGVSVPEERQSTVKKEKSGSQQPNKVIDKNKMQRANS
  VTVDGQGLQVTPVPGTHPLLVFVNPKSGGKQGERIYRKFQYLLNPRQVYSLSGNGPMPGL
  NFFRDVPDFRVLACGGDGTVGWVLDCIEKANVGKHPPVAILPLGTGNDLARCLRWGGGYE
  GENLMKILKDIENSTEIMLDRWKFEVIPNDKDEKGDPVPYSIINNYFSIGVDASIAHRFH
  IMREKHPEKFNSRMKNKFWYFEFGTSETFSATCKKLHESVEIECDGVQIDLINISLEGIA
  ILNIPSMHGGSNLWGESKKRRSHRRIEKKGSDKRTTVTDAKELKFASQDLSDQLLEVVGL
  EGAMEMGQIYTGLKSAGRRLAQCSCVVIRTSKSLPMQIDGEPWMQTPCTIKITHKNQAPM
  LMGPPPKTGLFCSLVKRTRNRSKE
• 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). Has a higher activity with long-chain diacylglycerols like 1,2-di-(9Z-octadecenoyl)-sn-glycerol compared to 1,2-didecanoyl-sn-glycerol. Specifically expressed in brain, it regulates neuron-specific morphological changes including neurite branching and neurite spine formation; [Isoform 2]: Does not associate with membranes but has a diacylglycerol kinase activity.
• Tissue Specificity: .Specifically expressed in brain but also detected in uterus . In adult brain, expressed in the amygdala, caudate nucleus, and hippocampus .; [Isoform 2]: More ubiquitously expressed but at lower level compared to isoform 1.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[4]
Depression	DIS3XJ69	Strong	Biomarker	[2]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[5]
Mitochondrial DNA depletion syndrome	DISIGZSM	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[8]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[1]
Asthma	DISW9QNS	Disputed	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[11]

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 beta (DGKB).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Diacylglycerol kinase beta (DGKB).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Diacylglycerol kinase beta (DGKB).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Diacylglycerol kinase beta (DGKB).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Diacylglycerol kinase beta (DGKB).	[18]

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 decreases the methylation of Diacylglycerol kinase beta (DGKB).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Diacylglycerol kinase beta (DGKB).	[17]

References

• [1] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [2] Diacylglycerol kinase knockout mice exhibit lithium-sensitive behavioral abnormalities.PLoS One. 2010 Oct 18;5(10):e13447. doi: 10.1371/journal.pone.0013447.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Identification and characterization of novel fusion genes in prostate cancer by targeted RNA capture and next-generation sequencing.Acta Biochim Biophys Sin (Shanghai). 2018 Nov 1;50(11):1166-1172. doi: 10.1093/abbs/gmy112.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [15] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [16] 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.
• [17] 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.
• [18] 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.