Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8OEPYT)

• DOT Name: Diacylglycerol kinase theta (DGKQ)
• Synonyms: DAG kinase theta; DGKtheta; EC 2.7.1.107; EC 2.7.1.93; Diglyceride kinase theta; DGK-theta
• Gene Name: DGKQ
• Related Disease:
  Type-1/2 diabetes
  Alzheimer disease
  Myositis disease
  Primary biliary cholangitis
  Rheumatoid arthritis
  Sjogren syndrome
  Systemic lupus erythematosus
  Systemic sclerosis
  Parkinson disease
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
• UniProt ID: DGKQ_HUMAN
• EC Number: 2.7.1.107; 2.7.1.93
• Pfam ID: PF00130 ; PF00609 ; PF00781 ; PF00788
• Sequence:
  MAAAAEPGARAWLGGGSPRPGSPACSPVLGSGGRARPGPGPGPGPERAGVRAPGPAAAPG
  HSFRKVTLTKPTFCHLCSDFIWGLAGFLCDVCNFMSHEKCLKHVRIPCTSVAPSLVRVPV
  AHCFGPRGLHKRKFCAVCRKVLEAPALHCEVCELHLHPDCVPFACSDCRQCHQDGHQDHD
  THHHHWREGNLPSGARCEVCRKTCGSSDVLAGVRCEWCGVQAHSLCSAALAPECGFGRLR
  SLVLPPACVRLLPGGFSKTQSFRIVEAAEPGEGGDGADGSAAVGPGRETQATPESGKQTL
  KIFDGDDAVRRSQFRLVTVSRLAGAEEVLEAALRAHHIPEDPGHLELCRLPPSSQACDAW
  AGGKAGSAVISEEGRSPGSGEATPEAWVIRALPRAQEVLKIYPGWLKVGVAYVSVRVTPK
  STARSVVLEVLPLLGRQAESPESFQLVEVAMGCRHVQRTMLMDEQPLLDRLQDIRQMSVR
  QVSQTRFYVAESRDVAPHVSLFVGGLPPGLSPEEYSSLLHEAGATKATVVSVSHIYSSQG
  AVVLDVACFAEAERLYMLLKDMAVRGRLLTALVLPDLLHAKLPPDSCPLLVFVNPKSGGL
  KGRDLLCSFRKLLNPHQVFDLTNGGPLPGLHLFSQVPCFRVLVCGGDGTVGWVLGALEET
  RYRLACPEPSVAILPLGTGNDLGRVLRWGAGYSGEDPFSVLLSVDEADAVLMDRWTILLD
  AHEAGSAENDTADAEPPKIVQMSNYCGIGIDAELSLDFHQAREEEPGKFTSRLHNKGVYV
  RVGLQKISHSRSLHKQIRLQVERQEVELPSIEGLIFINIPSWGSGADLWGSDSDTRFEKP
  RMDDGLLEVVGVTGVVHMGQVQGGLRSGIRIAQGSYFRVTLLKATPVQVDGEPWVQAPGH
  MIISAAGPKVHMLRKAKQKPRRAGTTRDARADAAPAPESDPR
• 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. Within the adrenocorticotropic hormone signaling pathway, produces phosphatidic acid which in turn activates NR5A1 and subsequent steroidogenic gene transcription. Also functions downstream of the nerve growth factor signaling pathway being specifically activated in the nucleus by the growth factor. Through its diacylglycerol activity also regulates synaptic vesicle endocytosis.
• 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
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[3]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[3]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[3]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[3]
Parkinson disease	DISQVHKL	moderate	Biomarker	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[7]
Liver cancer	DISDE4BI	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Diacylglycerol kinase theta (DGKQ).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Diacylglycerol kinase theta (DGKQ).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Diacylglycerol kinase theta (DGKQ).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Diacylglycerol kinase theta (DGKQ).	[11]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Diacylglycerol kinase theta (DGKQ).	[12]

References

• [1] Establishment of a DGK Endogenous Promoter Luciferase Reporter HepG2 Cell Line for Studying the Transcriptional Regulation of DGK Gene.Appl Biochem Biotechnol. 2019 Apr;187(4):1344-1355. doi: 10.1007/s12010-018-2890-4. Epub 2018 Sep 19.
• [2] Association of Parkinson's Disease GWAS-Linked Loci with Alzheimer's Disease in Han Chinese.Mol Neurobiol. 2017 Jan;54(1):308-318. doi: 10.1007/s12035-015-9649-5. Epub 2016 Jan 6.
• [3] Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases.Ann Rheum Dis. 2019 Mar;78(3):311-319. doi: 10.1136/annrheumdis-2018-214127. Epub 2018 Dec 20.
• [4] International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.Nat Commun. 2015 Sep 22;6:8019. doi: 10.1038/ncomms9019.
• [5] Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjgren's syndrome.Nat Genet. 2013 Nov;45(11):1284-92. doi: 10.1038/ng.2792. Epub 2013 Oct 6.
• [6] Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.Ann Neurol. 2020 Jan;87(1):139-153. doi: 10.1002/ana.25629. Epub 2019 Nov 18.
• [7] Establishment of a novel hepatic steatosis cell model by Cas9/sgRNA-mediated DGK gene knockout.Mol Med Rep. 2018 Feb;17(2):2169-2176. doi: 10.3892/mmr.2017.8140. Epub 2017 Nov 22.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.