Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBL32T3)

• DOT Name: Diacylglycerol kinase gamma (DGKG)
• Synonyms: DAG kinase gamma; EC 2.7.1.107; Diglyceride kinase gamma; DGK-gamma
• Gene Name: DGKG
• Related Disease:
  Autosomal dominant optic atrophy, classic form
  Colorectal carcinoma
  Disorder of orbital region
  Major depressive disorder
  Mood disorder
  Neoplasm
  Obesity
  Urticaria
  Advanced cancer
  Asthma
  Hepatocellular carcinoma
• UniProt ID: DGKG_HUMAN
• EC Number: 2.7.1.107
• Pfam ID: PF00130 ; PF14513 ; PF00609 ; PF00781 ; PF13499
• Sequence:
  MGEERWVSLTPEEFDQLQKYSEYSSKKIKDALTEFNEGGSLKQYDPHEPISYDVFKLFMR
  AYLEVDLPQPLSTHLFLAFSQKPRHETSDHPTEGASNSEANSADTNIQNADNATKADEAC
  APDTESNMAEKQAPAEDQVAATPLEPPVPRSSSSESPVVYLKDVVCYLSLLETGRPQDKL
  EFMFRLYDSDENGLLDQAEMDCIVNQMLHIAQYLEWDPTELRPILKEMLQGMDYDRDGFV
  SLQEWVHGGMTTIPLLVLLGMDDSGSKGDGRHAWTMKHFKKPTYCNFCHIMLMGVRKQGL
  CCTYCKYTVHERCVSRNIPGCVKTYSKAKRSGEVMQHAWVEGNSSVKCDRCHKSIKCYQS
  VTARHCVWCRMTFHRKCELSTLCDGGELRDHILLPTSICPITRDRPGEKSDGCVSAKGEL
  VMQYKIIPTPGTHPLLVLVNPKSGGRQGERILRKFHYLLNPKQVFNLDNGGPTPGLNFFR
  DTPDFRVLACGGDGTVGWILDCIDKANFAKHPPVAVLPLGTGNDLARCLRWGGGYEGGSL
  TKILKDIEQSPLVMLDRWHLEVIPREEVENGDQVPYSIMNNYFSIGVDASIAHRFHVMRE
  KHPEKFNSRMKNKLWYFEFGTSETFAATCKKLHDHIELECDGVGVDLSNIFLEGIAILNI
  PSMYGGTNLWGENKKNRAVIRESRKGVTDPKELKFCVQDLSDQLLEVVGLEGAMEMGQIY
  TGLKSAGRRLAQCASVTIRTNKLLPMQVDGEPWMQPCCTIKITHKNQAPMMMGPPQKSSF
  FSLRRKSRSKD
• 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. Has no apparent specificity with regard to the acyl compositions of diacylglycerol. Specifically expressed in the cerebellum where it controls the level of diacylglycerol which in turn regulates the activity of protein kinase C gamma. Through protein kinase C gamma, indirectly regulates the dendritic development of Purkinje cells, cerebellar long term depression and ultimately cerebellar motor coordination.
• Tissue Specificity: Predominantly expressed in retina and in a much lesser extent in the brain. Other tissues contain extremely low levels of DGK-gamma.
• 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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Obesity	DIS47Y1K	Strong	Genetic Variation	[5]
Urticaria	DIS9WQAI	Strong	Altered Expression	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Asthma	DISW9QNS	Limited	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Diacylglycerol kinase gamma (DGKG).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Diacylglycerol kinase gamma (DGKG).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Diacylglycerol kinase gamma (DGKG).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Diacylglycerol kinase gamma (DGKG).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Diacylglycerol kinase gamma (DGKG).	[13]

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 gamma (DGKG).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Diacylglycerol kinase gamma (DGKG).	[14]

References

• [1] Mapping and genomic characterization of the gene encoding diacylglycerol kinase gamma (DAGK3): assessment of its role in dominant optic atrophy (OPA1).Hum Genet. 1999 Jan;104(1):99-105. doi: 10.1007/s004390050917.
• [2] 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.
• [3] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [4] Diacylglycerol kinase predicts prognosis and functions as a tumor suppressor by negatively regulating glucose transporter 1 in hepatocellular carcinoma.Exp Cell Res. 2018 Dec 15;373(1-2):211-220. doi: 10.1016/j.yexcr.2018.11.001. Epub 2018 Nov 3.
• [5] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.Nat Genet. 2013 May;45(5):501-12. doi: 10.1038/ng.2606. Epub 2013 Apr 7.
• [6] CREB5 computational regulation network construction and analysis between frontal cortex of HIV encephalitis (HIVE) and HIVE-control patients.Cell Biochem Biophys. 2011 Jul;60(3):199-207. doi: 10.1007/s12013-010-9140-x.
• [7] Analyses of shared genetic factors between asthma and obesity in children.J Allergy Clin Immunol. 2010 Sep;126(3):631-7.e1-8. doi: 10.1016/j.jaci.2010.06.030.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] 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.