Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0OMDEM)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3)
• Synonyms: EC 3.1.4.11; Phosphoinositide phospholipase C-beta-3; Phospholipase C-beta-3; PLC-beta-3
• Gene Name: PLCB3
• Related Disease:
  Adenocarcinoma
  Atopic dermatitis
  Cystic fibrosis
  Hyperparathyroidism
  Neuralgia
  Neuroendocrine neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Pulmonary disease
  Vitiligo
  High blood pressure
  Myocardial infarction
  Spondylometaphyseal dysplasia
  Spondylometaphyseal dysplasia with corneal dystrophy
  Type-1/2 diabetes
• UniProt ID: PLCB3_HUMAN
• PDB ID: 4GNK; 4QJ3; 4QJ4; 4QJ5; 7SQ2; 8EMV; 8EMW; 8EMX; 8UQN; 8UQO
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF09279 ; PF17787 ; PF00388 ; PF00387 ; PF08703
• Sequence:
  MAGAQPGVHALQLEPPTVVETLRRGSKFIKWDEETSSRNLVTLRVDPNGFFLYWTGPNME
  VDTLDISSIRDTRTGRYARLPKDPKIREVLGFGGPDARLEEKLMTVVSGPDPVNTVFLNF
  MAVQDDTAKVWSEELFKLAMNILAQNASRNTFLRKAYTKLKLQVNQDGRIPVKNILKMFS
  ADKKRVETALESCGLKFNRSESIRPDEFSLEIFERFLNKLCLRPDIDKILLEIGAKGKPY
  LTLEQLMDFINQKQRDPRLNEVLYPPLRPSQARLLIEKYEPNQQFLERDQMSMEGFSRYL
  GGEENGILPLEALDLSTDMTQPLSAYFINSSHNTYLTAGQLAGTSSVEMYRQALLWGCRC
  VELDVWKGRPPEEEPFITHGFTMTTEVPLRDVLEAIAETAFKTSPYPVILSFENHVDSAK
  QQAKMAEYCRSIFGDALLIEPLDKYPLAPGVPLPSPQDLMGRILVKNKKRHRPSAGGPDS
  AGRKRPLEQSNSALSESSAATEPSSPQLGSPSSDSCPGLSNGEEVGLEKPSLEPQKSLGD
  EGLNRGPYVLGPADREDEEEDEEEEEQTDPKKPTTDEGTASSEVNATEEMSTLVNYIEPV
  KFKSFEAARKRNKCFEMSSFVETKAMEQLTKSPMEFVEYNKQQLSRIYPKGTRVDSSNYM
  PQLFWNVGCQLVALNFQTLDVAMQLNAGVFEYNGRSGYLLKPEFMRRPDKSFDPFTEVIV
  DGIVANALRVKVISGQFLSDRKVGIYVEVDMFGLPVDTRRKYRTRTSQGNSFNPVWDEEP
  FDFPKVVLPTLASLRIAAFEEGGKFVGHRILPVSAIRSGYHYVCLRNEANQPLCLPALLI
  YTEASDYIPDDHQDYAEALINPIKHVSLMDQRARQLAALIGESEAQAGQETCQDTQSQQL
  GSQPSSNPTPSPLDASPRRPPGPTTSPASTSLSSPGQRDDLIASILSEVAPTPLDELRGH
  KALVKLRSRQERDLRELRKKHQRKAVTLTRRLLDGLAQAQAEGRCRLRPGALGGAADVED
  TKEGEDEAKRYQEFQNRQVQSLLELREAQVDAEAQRRLEHLRQALQRLREVVLDANTTQF
  KRLKEMNEREKKELQKILDRKRHNSISEAKMRDKHKKEAELTEINRRHITESVNSIRRLE
  EAQKQRHDRLVAGQQQVLQQLAEEEPKLLAQLAQECQEQRARLPQEIRRSLLGEMPEGLG
  DGPLVACASNGHAPGSSGHLSGADSESQEENTQL
• Function: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Chemokine sig.ling pathway (hsa04062)
  Phosphatidylinositol sig.ling system (hsa04070)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Wnt sig.ling pathway (hsa04310)
  Apelin sig.ling pathway (hsa04371)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  NOD-like receptor sig.ling pathway (hsa04621)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Taste transduction (hsa04742)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone sig.ling pathway (hsa04919)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Carbohydrate digestion and absorption (hsa04973)
  Alzheimer disease (hsa05010)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Amoebiasis (hsa05146)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
  Acetylcholine regulates insulin secretion (R-HSA-399997)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G beta (R-HSA-418217)
  Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion (R-HSA-434316)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  PLC beta mediated events (R-HSA-112043)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[2]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[3]
Hyperparathyroidism	DIS4FVAT	Strong	Altered Expression	[4]
Neuralgia	DISWO58J	Strong	Biomarker	[5]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[3]
Vitiligo	DISR05SL	Strong	Genetic Variation	[8]
High blood pressure	DISY2OHH	Limited	Biomarker	[9]
Myocardial infarction	DIS655KI	Limited	Biomarker	[10]
Spondylometaphyseal dysplasia	DISDTAJK	Limited	Autosomal recessive	[11]
Spondylometaphyseal dysplasia with corneal dystrophy	DISI1AJK	Limited	Unknown	[11]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[12]

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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3).	[19]

References

• [1] Distinct Prognostic Values of Phospholipase C Beta Family Members for Non-Small Cell Lung Carcinoma.Biomed Res Int. 2019 Apr 7;2019:4256524. doi: 10.1155/2019/4256524. eCollection 2019.
• [2] Critical role for mast cell Stat5 activity in skin inflammation.Cell Rep. 2014 Jan 30;6(2):366-76. doi: 10.1016/j.celrep.2013.12.029. Epub 2014 Jan 9.
• [3] PLCB3 Loss of Function Reduces Pseudomonas aeruginosa-Dependent IL-8 Release in Cystic Fibrosis.Am J Respir Cell Mol Biol. 2018 Oct;59(4):428-436. doi: 10.1165/rcmb.2017-0267OC.
• [4] Hyperparathyroidism of multiple endocrine neoplasia type 1: candidate gene and parathyroid calcium sensing protein expression.Surgery. 1995 Dec;118(6):924-30; discussion 930-1. doi: 10.1016/s0039-6060(05)80095-9.
• [5] Phospholipase C{beta}3 in mouse and human dorsal root ganglia and spinal cord is a possible target for treatment of neuropathic pain.Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):20004-8. doi: 10.1073/pnas.0810899105. Epub 2008 Dec 9.
• [6] In situ RNA-RNA hybridisation of phospholipase C beta 3 shows lack of expression in neuroendocrine tumours.Anticancer Res. 2003 May-Jun;23(3B):2227-32.
• [7] Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.
• [8] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [9] Aortic constriction induces hypertension and cardiac hypertrophy via (pro)renin receptor activation and the PLC? signaling pathway.Mol Med Rep. 2019 Jan;19(1):573-580. doi: 10.3892/mmr.2018.9653. Epub 2018 Nov 13.
• [10] Expression of Gq alpha and PLC-beta in scar and border tissue in heart failure due to myocardial infarction.Circulation. 1998 Mar 10;97(9):892-9. doi: 10.1161/01.cir.97.9.892.
• [11] Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy. J Med Genet. 2018 Feb;55(2):122-130. doi: 10.1136/jmedgenet-2017-104827. Epub 2017 Nov 9.
• [12] The role of CNP-mediated PKG/PKA-PLC pathway in diabetes-induced gastric motility disorder.Peptides. 2018 Dec;110:47-55. doi: 10.1016/j.peptides.2018.10.012. Epub 2018 Nov 1.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.