Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1S9869)

• DOT Name: Diacylglycerol lipase-beta (DAGLB)
• Synonyms: DAGL-beta; DGL-beta; EC 3.1.1.116; KCCR13L; PUFA-specific triacylglycerol lipase; EC 3.1.1.3; Sn1-specific diacylglycerol lipase beta
• Gene Name: DAGLB
• UniProt ID: DGLB_HUMAN
• EC Number: 3.1.1.116; 3.1.1.3
• Pfam ID: PF01764
• Sequence:
  MPGMVLFGRRWAIASDDLVFPGFFELVVRVLWWIGILTLYLMHRGKLDCAGGALLSSYLI
  VLMILLAVVICTVSAIMCVSMRGTICNPGPRKSMSKLLYIRLALFFPEMVWASLGAAWVA
  DGVQCDRTVVNGIIATVVVSWIIIAATVVSIIIVFDPLGGKMAPYSSAGPSHLDSHDSSQ
  LLNGLKTAATSVWETRIKLLCCCIGKDDHTRVAFSSTAELFSTYFSDTDLVPSDIAAGLA
  LLHQQQDNIRNNQEPAQVVCHAPGSSQEADLDAELENCHHYMQFAAAAYGWPLYIYRNPL
  TGLCRIGGDCCRSRTTDYDLVGGDQLNCHFGSILHTTGLQYRDFIHVSFHDKVYELPFLV
  ALDHRKESVVVAVRGTMSLQDVLTDLSAESEVLDVECEVQDRLAHKGISQAARYVYQRLI
  NDGILSQAFSIAPEYRLVIVGHSLGGGAAALLATMLRAAYPQVRCYAFSPPRGLWSKALQ
  EYSQSFIVSLVLGKDVIPRLSVTNLEDLKRRILRVVAHCNKPKYKILLHGLWYELFGGNP
  NNLPTELDGGDQEVLTQPLLGEQSLLTRWSPAYSFSSDSPLDSSPKYPPLYPPGRIIHLQ
  EEGASGRFGCCSAAHYSAKWSHEAEFSKILIGPKMLTDHMPDILMRALDSVVSDRAACVS
  CPAQGVSSVDVA
• Function: Lipase that catalyzes the hydrolysis of arachidonic acid (AA)-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG) which can be further cleaved by downstream enzymes to release arachidonic acid (AA) for cyclooxygenase (COX)-mediated eicosanoid production. Preferentially hydrolyzes DAGs at the sn-1 position in a calcium-dependent manner and has negligible activity against other lipids including monoacylglycerols and phospholipids. Plays a key role in the regulation of 2-AG and AA pools utilized by COX1/2 to generate lipid mediators of macrophage and microglia inflammatory responses. Functions also as a polyunsaturated fatty acids-specific triacylglycerol lipase in macrophages. Plays an important role to support the metabolic and signaling demands of macrophages.
• KEGG Pathway:
  Retrograde endocan.binoid sig.ling (hsa04723)
  Aldosterone synthesis and secretion (hsa04925)
• Reactome Pathway: Arachidonate production from DAG (R-HSA-426048)
• BioCyc Pathway: MetaCyc:ENSG00000164535-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Diacylglycerol lipase-beta (DAGLB).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Diacylglycerol lipase-beta (DAGLB).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Diacylglycerol lipase-beta (DAGLB).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Diacylglycerol lipase-beta (DAGLB).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Diacylglycerol lipase-beta (DAGLB).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Diacylglycerol lipase-beta (DAGLB).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Diacylglycerol lipase-beta (DAGLB).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Diacylglycerol lipase-beta (DAGLB).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Diacylglycerol lipase-beta (DAGLB).	[9]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Diacylglycerol lipase-beta (DAGLB).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Diacylglycerol lipase-beta (DAGLB).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Diacylglycerol lipase-beta (DAGLB).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Diacylglycerol lipase-beta (DAGLB).	[15]
ACEA	DMWX3HT	Investigative	ACEA increases the expression of Diacylglycerol lipase-beta (DAGLB).	[16]

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 increases the methylation of Diacylglycerol lipase-beta (DAGLB).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Diacylglycerol lipase-beta (DAGLB).	[14]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] 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.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [9] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [10] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [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] 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.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] An inverse agonist of estrogen-related receptor regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice. Arch Toxicol. 2020 Feb;94(2):427-438. doi: 10.1007/s00204-019-02648-7. Epub 2020 Jan 7.