Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8GVKGM)

• DOT Name: Diacylglycerol lipase-alpha (DAGLA)
• Synonyms: DAGL-alpha; DGL-alpha; EC 3.1.1.116; Neural stem cell-derived dendrite regulator; Sn1-specific diacylglycerol lipase alpha
• Gene Name: DAGLA
• UniProt ID: DGLA_HUMAN
• EC Number: 3.1.1.116
• Pfam ID: PF01764
• Sequence:
  MPGIVVFRRRWSVGSDDLVLPAIFLFLLHTTWFVILSVVLFGLVYNPHEACSLNLVDHGR
  GYLGILLSCMIAEMAIIWLSMRGGILYTEPRDSMQYVLYVRLAILVIEFIYAIVGIVWLT
  QYYTSCNDLTAKNVTLGMVVCNWVVILSVCITVLCVFDPTGRTFVKLRATKRRQRNLRTY
  NLRHRLEEGQATSWSRRLKVFLCCTRTKDSQSDAYSEIAYLFAEFFRDLDIVPSDIIAGL
  VLLRQRQRAKRNAVLDEANNDILAFLSGMPVTRNTKYLDLKNSQEMLRYKEVCYYMLFAL
  AAYGWPMYLMRKPACGLCQLARSCSCCLCPARPRFAPGVTIEEDNCCGCNAIAIRRHFLD
  ENMTAVDIVYTSCHDAVYETPFYVAVDHDKKKVVISIRGTLSPKDALTDLTGDAERLPVE
  GHHGTWLGHKGMVLSAEYIKKKLEQEMVLSQAFGRDLGRGTKHYGLIVVGHSLGAGTAAI
  LSFLLRPQYPTLKCFAYSPPGGLLSEDAMEYSKEFVTAVVLGKDLVPRIGLSQLEGFRRQ
  LLDVLQRSTKPKWRIIVGATKCIPKSELPEEVEVTTLASTRLWTHPSDLTIALSASTPLY
  PPGRIIHVVHNHPAEQCCCCEQEEPTYFAIWGDNKAFNEVIISPAMLHEHLPYVVMEGLN
  KVLENYNKGKTALLSAAKVMVSPTEVDLTPELIFQQQPLPTGPPMPTGLALELPTADHRN
  SSVRSKSQSEMSLEGFSEGRLLSPVVAAAARQDPVELLLLSTQERLAAELQARRAPLATM
  ESLSDTESLYSFDSRRSSGFRSIRGSPSLHAVLERDEGHLFYIDPAIPEENPSLSSRTEL
  LAADSLSKHSQDTQPLEAALGSGGVTPERPPSAAANDEEEEVGGGGGGPASRGELALHNG
  RLGDSPSPQVLEFAEFIDSLFNLDSKSSSFQDLYCMVVPESPTSDYAEGPKSPSQQEILL
  RAQFEPNLVPKPPRLFAGSADPSSGISLSPSFPLSSSGELMDLTPTGLSSQECLAADKIR
  TSTPTGHGASPAKQDELVISAR
• Function: Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG). Preferentially hydrolyzes sn-1 fatty acids from diacylglycerols (DAG) that contain arachidonic acid (AA) esterified at the sn-2 position to biosynthesize 2-AG. Has negligible activity against other lipids including monoacylglycerols and phospholipids. Plays a key role in regulating 2-AG signaling in the central nervous system (CNS). Regulates 2-AG involved in retrograde suppression at central synapses. Supports axonal growth during development and adult neurogenesis. Plays a role for eCB signaling in the physiological regulation of anxiety and depressive behaviors. Regulates also neuroinflammatory responses in the brain, in particular, LPS-induced microglial activation.
• Tissue Specificity: Highly expressed in brain and pancreas.
• 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:ENSG00000134780-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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 lipase-alpha (DAGLA).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Diacylglycerol lipase-alpha (DAGLA).	[7]

9 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-alpha (DAGLA).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Diacylglycerol lipase-alpha (DAGLA).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Diacylglycerol lipase-alpha (DAGLA).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Diacylglycerol lipase-alpha (DAGLA).	[5]
Orlistat	DMRJSP8	Approved	Orlistat decreases the activity of Diacylglycerol lipase-alpha (DAGLA).	[6]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Diacylglycerol lipase-alpha (DAGLA).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Diacylglycerol lipase-alpha (DAGLA).	[8]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Diacylglycerol lipase-alpha (DAGLA).	[9]
ACEA	DMWX3HT	Investigative	ACEA increases the expression of Diacylglycerol lipase-alpha (DAGLA).	[10]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [6] Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim Biophys Acta. 2006 Feb;1761(2):205-12. doi: 10.1016/j.bbalip.2005.12.009. Epub 2006 Jan 23.
• [7] 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.
• [8] 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.
• [9] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [10] 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.