Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDZ602D)

• DOT Name: Diacylglycerol kinase iota (DGKI)
• Synonyms: DAG kinase iota; DGK-iota; EC 2.7.1.107
• Gene Name: DGKI
• Related Disease:
  Acquired immune deficiency syndrome
  Adult glioblastoma
  Eclampsia
  Glioblastoma multiforme
  Neoplasm
  Schizophrenia
  Melanoma
  Retinopathy
• UniProt ID: DGKI_HUMAN
• EC Number: 2.7.1.107
• Pfam ID: PF12796 ; PF00130 ; PF00609 ; PF00781
• Sequence:
  MDAAGRGCHLLPLPAARGPARAPAAAAAAAASPPGPCSGAACAPSAAAGAGAMNPSSSAG
  EEKGATGGSSSSGSGAGSCCLGAEGGADPRGAGSAAAAGAAALDEPAAAGQKEKDEALEE
  KLRNLTFRKQVSYRKAISRAGLQHLAPAHPLSLPVANGPAKEPRATLDWSENAVNGEHLW
  LETNVSGDLCYLGEENCQVRFAKSALRRKCAVCKIVVHTACIEQLEKINFRCKPTFREGG
  SRSPRENFVRHHWVHRRRQEGKCKQCGKGFQQKFSFHSKEIVAISCSWCKQAFHNKVTCF
  MLHHIEEPCSLGAHAAVIVPPTWIIKVKKPQNSLKASNRKKKRTSFKRKASKRGMEQENK
  GRPFVIKPISSPLMKPLLVFVNPKSGGNQGTKVLQMFMWYLNPRQVFDLSQEGPKDALEL
  YRKVPNLRILACGGDGTVGWILSILDELQLSPQPPVGVLPLGTGNDLARTLNWGGGYTDE
  PVSKILCQVEDGTVVQLDRWNLHVERNPDLPPEELEDGVCKLPLNVFNNYFSLGFDAHVT
  LEFHESREANPEKFNSRFRNKMFYAGAAFSDFLQRSSRDLSKHVKVVCDGTDLTPKIQEL
  KFQCIVFLNIPRYCAGTMPWGNPGDHHDFEPQRHDDGYIEVIGFTMASLAALQVGGHGER
  LHQCREVMLLTYKSIPMQVDGEPCRLAPAMIRISLRNQANMVQKSKRRTSMPLLNDPQSV
  PDRLRIRVNKISLQDYEGFHYDKEKLREASISDWLRTIAGELVQSFGAIPLGILVVRGDC
  DLETCRMYIDRLQEDLQSVSSGSQRVHYQDHETSFPRALSAQRLSPRWCFLDDRSQEHLH
  FVMEISQDEIFILDPDMVVSQPAGTPPGMPDLVVEQASGISDWWNPALRKRMLSDSGLGM
  IAPYYEDSDLKDLSHSRVLQSPVSSEDHAILQAVIAGDLMKLIESYKNGGSLLIQGPDHC
  SLLHYAAKTGNGEIVKYILDHGPSELLDMADSETGETALHKAACQRNRAVCQLLVDAGAS
  LRKTDSKGKTPQERAQQAGDPDLAAYLESRQNYKVIGHEDLETAV
• 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 probably no preference for any of the diacylglycerols in terms of the acyl chain composition, especially for the acyl chain at the sn-2 position. By controlling the diacylglycerol/DAG-mediated activation of RASGRP3, negatively regulates the Rap1 signaling pathway. May play a role in presynaptic diacylglycerol/DAG signaling and control neurotransmitter release during metabotropic glutamate receptor-dependent long-term depression.
• Tissue Specificity: Specifically expressed in brain and retina . In brain, highly expressed in hippocampus, caudate nucleus, occipital pole, cerebral cortex, and cerebellum . Also detected in kidney .
• 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired immune deficiency syndrome	DISL5UOX	Strong	Genetic Variation	[1]
Adult glioblastoma	DISVP4LU	Strong	Posttranslational Modification	[2]
Eclampsia	DISWPO8U	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Posttranslational Modification	[2]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[5]
Retinopathy	DISB4B0F	Limited	Biomarker	[6]

9 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 iota (DGKI).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diacylglycerol kinase iota (DGKI).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Diacylglycerol kinase iota (DGKI).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Diacylglycerol kinase iota (DGKI).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Diacylglycerol kinase iota (DGKI).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Diacylglycerol kinase iota (DGKI).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diacylglycerol kinase iota (DGKI).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Diacylglycerol kinase iota (DGKI).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Diacylglycerol kinase iota (DGKI).	[7]

References

• [1] Genome-wide association study implicates PARD3B-based AIDS restriction.J Infect Dis. 2011 May 15;203(10):1491-502. doi: 10.1093/infdis/jir046.
• [2] DGKI methylation status modulates the prognostic value of MGMT in glioblastoma patients treated with combined radio-chemotherapy with temozolomide.PLoS One. 2014 Sep 18;9(9):e104455. doi: 10.1371/journal.pone.0104455. eCollection 2014.
• [3] Analysis of the Epigenome in Multiplex Pre-eclampsia Families Identifies SORD, DGKI, and ICA1 as Novel Candidate Risk Genes.Front Genet. 2019 Mar 19;10:227. doi: 10.3389/fgene.2019.00227. eCollection 2019.
• [4] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [5] Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition.Oncogene. 2017 Jun 8;36(23):3334-3345. doi: 10.1038/onc.2016.486. Epub 2017 Jan 16.
• [6] Evaluation of human diacylglycerol kinase(iota), DGKI, a homolog of Drosophila rdgA, in inherited retinopathy mapping to 7q.Mol Vis. 2000 Feb 22;6:6-9.
• [7] 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.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [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.