Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSBQR6D)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1)
• Synonyms: EC 3.1.4.11; PLC-148; Phosphoinositide phospholipase C-gamma-1; Phospholipase C-II; PLC-II; Phospholipase C-gamma-1; PLC-gamma-1
• Gene Name: PLCG1
• UniProt ID: PLCG1_HUMAN
• PDB ID: 1HSQ; 2HSP; 4EY0; 4FBN; 7NXE
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF00169 ; PF00388 ; PF00387 ; PF00017 ; PF00018
• Sequence:
  MAGAASPCANGCGPGAPSDAEVLHLCRSLEVGTVMTLFYSKKSQRPERKTFQVKLETRQI
  TWSRGADKIEGAIDIREIKEIRPGKTSRDFDRYQEDPAFRPDQSHCFVILYGMEFRLKTL
  SLQATSEDEVNMWIKGLTWLMEDTLQAPTPLQIERWLRKQFYSVDRNREDRISAKDLKNM
  LSQVNYRVPNMRFLRERLTDLEQRSGDITYGQFAQLYRSLMYSAQKTMDLPFLEASTLRA
  GERPELCRVSLPEFQQFLLDYQGELWAVDRLQVQEFMLSFLRDPLREIEEPYFFLDEFVT
  FLFSKENSVWNSQLDAVCPDTMNNPLSHYWISSSHNTYLTGDQFSSESSLEAYARCLRMG
  CRCIELDCWDGPDGMPVIYHGHTLTTKIKFSDVLHTIKEHAFVASEYPVILSIEDHCSIA
  QQRNMAQYFKKVLGDTLLTKPVEISADGLPSPNQLKRKILIKHKKLAEGSAYEEVPTSMM
  YSENDISNSIKNGILYLEDPVNHEWYPHYFVLTSSKIYYSEETSSDQGNEDEEEPKEVSS
  STELHSNEKWFHGKLGAGRDGRHIAERLLTEYCIETGAPDGSFLVRESETFVGDYTLSFW
  RNGKVQHCRIHSRQDAGTPKFFLTDNLVFDSLYDLITHYQQVPLRCNEFEMRLSEPVPQT
  NAHESKEWYHASLTRAQAEHMLMRVPRDGAFLVRKRNEPNSYAISFRAEGKIKHCRVQQE
  GQTVMLGNSEFDSLVDLISYYEKHPLYRKMKLRYPINEEALEKIGTAEPDYGALYEGRNP
  GFYVEANPMPTFKCAVKALFDYKAQREDELTFIKSAIIQNVEKQEGGWWRGDYGGKKQLW
  FPSNYVEEMVNPVALEPEREHLDENSPLGDLLRGVLDVPACQIAIRPEGKNNRLFVFSIS
  MASVAHWSLDVAADSQEELQDWVKKIREVAQTADARLTEGKIMERRKKIALELSELVVYC
  RPVPFDEEKIGTERACYRDMSSFPETKAEKYVNKAKGKKFLQYNRLQLSRIYPKGQRLDS
  SNYDPLPMWICGSQLVALNFQTPDKPMQMNQALFMTGRHCGYVLQPSTMRDEAFDPFDKS
  SLRGLEPCAISIEVLGARHLPKNGRGIVCPFVEIEVAGAEYDSTKQKTEFVVDNGLNPVW
  PAKPFHFQISNPEFAFLRFVVYEEDMFSDQNFLAQATFPVKGLKTGYRAVPLKNNYSEDL
  ELASLLIKIDIFPAKENGDLSPFSGTSLRERGSDASGQLFHGRAREGSFESRYQQPFEDF
  RISQEHLADHFDSRERRAPRRTRVNGDNRL
• Function: Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, EGFR, FGFR1, FGFR2, FGFR3 and FGFR4. Plays a role in actin reorganization and cell migration. Guanine nucleotide exchange factor that binds the GTPase DNM1 and catalyzes the dissociation of GDP, allowing a GTP molecule to bind in its place, therefore enhancing DNM1-dependent endocytosis.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  Chemokine sig.ling pathway (hsa04062)
  NF-kappa B sig.ling pathway (hsa04064)
  HIF-1 sig.ling pathway (hsa04066)
  Phosphatidylinositol sig.ling system (hsa04070)
  Phospholipase D sig.ling pathway (hsa04072)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Neutrophil extracellular trap formation (hsa04613)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Leukocyte transendothelial migration (hsa04670)
  Neurotrophin sig.ling pathway (hsa04722)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Thyroid hormone sig.ling pathway (hsa04919)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Growth hormone synthesis, secretion and action (hsa04935)
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Vibrio cholerae infection (hsa05110)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Shigellosis (hsa05131)
  Yersinia infection (hsa05135)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroR.s in cancer (hsa05206)
  Glioma (hsa05214)
  Non-small cell lung cancer (hsa05223)
  Hepatocellular carcinoma (hsa05225)
  Choline metabolism in cancer (hsa05231)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  (FGFR2)
  (FGFR3)
  (FGFR4)
  Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants (R-HSA-1236382)
  PLCG1 events in ERBB2 signaling (R-HSA-1251932)
  DAG and IP3 signaling (R-HSA-1489509)
  PLC-gamma1 signalling (R-HSA-167021)
  Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
  Downstream signal transduction (R-HSA-186763)
  Signaling by ALK (R-HSA-201556)
  Generation of second messenger molecules (R-HSA-202433)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  PECAM1 interactions (R-HSA-210990)
  EGFR interacts with phospholipase C-gamma (R-HSA-212718)
  DAP12 signaling (R-HSA-2424491)
  FCERI mediated MAPK activation (R-HSA-2871796)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  Role of second messengers in netrin-1 signaling (R-HSA-418890)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  Constitutive Signaling by EGFRvIII (R-HSA-5637810)
  Phospholipase C-mediated cascade (R-HSA-5654219)
  Phospholipase C-mediated cascade (R-HSA-5654221)
  Phospholipase C-mediated cascade (R-HSA-5654227)
  Phospholipase C-mediated cascade (R-HSA-5654228)
  Signaling by FGFR2 in disease (R-HSA-5655253)
  Signaling by FGFR4 in disease (R-HSA-5655291)
  Signaling by FGFR1 in disease (R-HSA-5655302)
  Signaling by FGFR3 in disease (R-HSA-5655332)
  RET signaling (R-HSA-8853659)
  Activated NTRK2 signals through PLCG1 (R-HSA-9026527)
  Erythropoietin activates Phospholipase C gamma (PLCG) (R-HSA-9027277)
  Activated NTRK3 signals through PLCG1 (R-HSA-9034793)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Signaling by ERBB2 ECD mutants (R-HSA-9665348)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1) decreases the response to substance of Fluorouracil.	[20]

5 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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[5]
Procaine	DM4LSNE	Approved	Procaine increases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[14]
Mepacrine	DMU8L7C	Investigative	Mepacrine decreases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[7]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[17]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[17]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Chrysin	DM7V2LG	Investigative	Chrysin increases the degradation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCG1).	[18]

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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [8] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [9] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [10] H(1)R mediates local anesthetic-induced vascular permeability in angioedema. Toxicol Appl Pharmacol. 2020 Apr 1;392:114921. doi: 10.1016/j.taap.2020.114921. Epub 2020 Feb 12.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [13] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [18] Bcl-2 attenuates anticancer agents-induced apoptosis by sustained activation of Akt/protein kinase B in U937 cells. Apoptosis. 2005 Dec;10(6):1333-43. doi: 10.1007/s10495-005-2763-5.
• [19] Quinacrine is active in preclinical models of glioblastoma through suppressing angiogenesis, inducing oxidative stress and activating AMPK. Toxicol In Vitro. 2022 Sep;83:105420. doi: 10.1016/j.tiv.2022.105420. Epub 2022 Jun 17.
• [20] Antitumour effects on human colorectal carcinomas cells by stable silencing of phospholipase C-gamma 1 with lentivirus-delivered siRNA. Chin Med J (Engl). 2007 May 5;120(9):749-54.