Details of Drug Off-Target (DOT)

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

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1)
• Synonyms: EC 3.1.4.11; Pancreas-enriched phospholipase C; Phosphoinositide phospholipase C-epsilon-1; Phospholipase C-epsilon-1; PLC-epsilon-1
• Gene Name: PLCE1
• Related Disease:
  Nephrotic syndrome, type 3
  Adenocarcinoma
  Advanced cancer
  Bladder cancer
  Carcinoma
  Cardiovascular disease
  Chronic obstructive pulmonary disease
  Chronic renal failure
  Cytochrome-c oxidase deficiency disease
  Esophageal adenocarcinoma
  Esophagitis
  Familial multiple trichoepithelioma
  Focal segmental glomerulosclerosis
  Gastric cancer
  Gastric neoplasm
  Gastritis
  Head-neck squamous cell carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Nephrotic syndrome, type 2
  Open-angle glaucoma
  Squamous cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  End-stage renal disease
  Gastric adenocarcinoma
  High blood pressure
  Lung cancer
  Lung carcinoma
  Nephrotic syndrome
  Familial idiopathic steroid-resistant nephrotic syndrome
  Acute myelogenous leukaemia
  Familial nephrotic syndrome
  Human papillomavirus infection
  Migraine disorder
  Myelodysplastic syndrome
  Steroid-resistant nephrotic syndrome
  Wilms tumor
• UniProt ID: PLCE1_HUMAN
• PDB ID: 2BYE; 2BYF; 2C5L
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF09279 ; PF00388 ; PF00387 ; PF00788 ; PF00617
• Sequence:
  MTSEEMTASVLIPVTQRKVVSAQSAADESSEKVSDINISKAHTVRRSGETSHTISQLNKL
  KEEPSGSNLPKILSIAREKIVSDENSNEKCWEKIMPDSAKNLNINCNNILRNHQHGLPQR
  QFYEMYNSVAEEDLCLETGIPSPLERKVFPGIQLELDRPSMGISPLGNQSVIIETGRAHP
  DSRRAVFHFHYEVDRRMSDTFCTLSENLILDDCGNCVPLPGGEEKQKKNYVAYTCKLMEL
  AKNCDNKNEQLQCDHCDTLNDKYFCFEGSCEKVDMVYSGDSFCRKDFTDSQAAKTFLSHF
  EDFPDNCDDVEEDAFKSKKERSTLLVRRFCKNDREVKKSVYTGTRAIVRTLPSGHIGLTA
  WSYIDQKRNGPLLPCGRVMEPPSTVEIRQDGSQRLSEAQWYPIYNAVRREETENTVGSLL
  HFLTKLPASETAHGRISVGPCLKQCVRDTVCEYRATLQRTSISQYITGSLLEATTSLGAR
  SGLLSTFGGSTGRMMLKERQPGPSVANSNALPSSSAGISKELIDLQPLIQFPEEVASILM
  EQEQTIYRRVLPVDYLCFLTRDLGTPECQSSLPCLKASISASILTTQNGEHNALEDLVMR
  FNEVSSWVTWLILTAGSMEEKREVFSYLVHVAKCCWNMGNYNAVMEFLAGLRSRKVLKMW
  QFMDQSDIETMRSLKDAMAQHESSCEYRKVVTRALHIPGCKVVPFCGVFLKELCEVLDGA
  SGLMKLCPRYNSQEETLEFVADYSGQDNFLQRVGQNGLKNSEKESTVNSIFQVIRSCNRS
  LETDEEDSPSEGNSSRKSSLKDKSRWQFIIGDLLDSDNDIFEQSKEYDSHGSEDSQKAFD
  HGTELIPWYVLSIQADVHQFLLQGATVIHYDQDTHLSARCFLQLQPDNSTLTWVKPTTAS
  PASSKAKLGVLNNTAEPGKFPLLGNAGLSSLTEGVLDLFAVKAVYMGHPGIDIHTVCVQN
  KLGSMFLSETGVTLLYGLQTTDNRLLHFVAPKHTAKMLFSGLLELTRAVRKMRKFPDQRQ
  QWLRKQYVSLYQEDGRYEGPTLAHAVELFGGRRWSARNPSPGTSAKNAEKPNMQRNNTLG
  ISTTKKKKKILMRGESGEVTDDEMATRKAKMHKECRSRSGSDPQDINEQEESEVNAIANP
  PNPLPSRRAHSLTTAGSPNLAAGTSSPIRPVSSPVLSSSNKSPSSAWSSSSWHGRIKGGM
  KGFQSFMVSDSNMSFVEFVELFKSFSVRSRKDLKDLFDVYAVPCNRSGSESAPLYTNLTI
  DENTSDLQPDLDLLTRNVSDLGLFIKSKQQLSDNQRQISDAIAAASIVTNGTGIESTSLG
  IFGVGILQLNDFLVNCQGEHCTYDEILSIIQKFEPSISMCHQGLMSFEGFARFLMDKENF
  ASKNDESQENIKELQLPLSYYYIESSHNTYLTGHQLKGESSVELYSQVLLQGCRSVELDC
  WDGDDGMPIIYHGHTLTTKIPFKEVVEAIDRSAFINSDLPIIISIENHCSLPQQRKMAEI
  FKTVFGEKLVTKFLFETDFSDDPMLPSPDQLRKKVLLKNKKLKAHQTPVDILKQKAHQLA
  SMQVQAYNGGNANPRPANNEEEEDEEDEYDYDYESLSDDNILEDRPENKSCNDKLQFEYN
  EEIPKRIKKADNSACNKGKVYDMELGEEFYLDQNKKESRQIAPELSDLVIYCQAVKFPGL
  STLNASGSSRGKERKSRKSIFGNNPGRMSPGETASFNKTSGKSSCEGIRQTWEESSSPLN
  PTTSLSAIIRTPKCYHISSLNENAAKRLCRRYSQKLTQHTACQLLRTYPAATRIDSSNPN
  PLMFWLHGIQLVALNYQTDDLPLHLNAAMFEANGGCGYVLKPPVLWDKNCPMYQKFSPLE
  RDLDSMDPAVYSLTIVSGQNVCPSNSMGSPCIEVDVLGMPLDSCHFRTKPIHRNTLNPMW
  NEQFLFHVHFEDLVFLRFAVVENNSSAVTAQRIIPLKALKRGYRHLQLRNLHNEVLEISS
  LFINSRRMEENSSGNTMSASSMFNTEERKCLQTHRVTVHGVPGPEPFTVFTINGGTKAKQ
  LLQQILTNEQDIKPVTTDYFLMEEKYFISKEKNECRKQPFQRAIGPEEEIMQILSSWFPE
  EGYMGRIVLKTQQENLEEKNIVQDDKEVILSSEEESFFVQVHDVSPEQPRTVIKAPRVST
  AQDVIQQTLCKAKYSYSILSNPNPSDYVLLEEVVKDTTNKKTTTPKSSQRVLLDQECVFQ
  AQSKWKGAGKFILKLKEQVQASREDKKKGISFASELKKLTKSTKQPRGLTSPSQLLTSES
  IQTKEEKPVGGLSSSDTMDYRQ
• 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. PLCE1 is a bifunctional enzyme which also regulates small GTPases of the Ras superfamily through its Ras guanine-exchange factor (RasGEF) activity. As an effector of heterotrimeric and small G-protein, it may play a role in cell survival, cell growth, actin organization and T-cell activation. In podocytes, is involved in the regulation of lamellipodia formation. Acts downstream of AVIL to allow ARP2/3 complex assembly.
• Tissue Specificity: Widely expressed. Expressed in podocytes .; [Isoform 1]: Broadly expressed and only absent in peripheral blood leukocytes.; [Isoform 2]: Specifically expressed in placenta, lung and spleen.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Phosphatidylinositol sig.ling system (hsa04070)
  Thyroid hormone sig.ling pathway (hsa04919)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Shigellosis (hsa05131)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway: Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
• BioCyc Pathway: MetaCyc:HS06473-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephrotic syndrome, type 3	DISJKB7I	Definitive	Autosomal recessive	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[7]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[8]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Genetic Variation	[9]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[10]
Esophagitis	DISHVC9B	Strong	Altered Expression	[11]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Genetic Variation	[10]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[12]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[3]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[13]
Gastritis	DIS8G07K	Strong	Genetic Variation	[14]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[15]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[16]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[13]
Nephrotic syndrome, type 2	DISIRFO1	Strong	GermlineCausalMutation	[17]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[18]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[19]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
End-stage renal disease	DISXA7GG	moderate	Genetic Variation	[8]
Gastric adenocarcinoma	DISWWLTC	moderate	Altered Expression	[20]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[21]
Lung cancer	DISCM4YA	moderate	Altered Expression	[22]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[22]
Nephrotic syndrome	DISSPSC2	moderate	Genetic Variation	[23]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[17]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Genetic Variation	[24]
Familial nephrotic syndrome	DISADF8G	Limited	Genetic Variation	[25]
Human papillomavirus infection	DISX61LX	Limited	Genetic Variation	[26]
Migraine disorder	DISFCQTG	Limited	Genetic Variation	[27]
Myelodysplastic syndrome	DISYHNUI	Limited	Genetic Variation	[24]
Steroid-resistant nephrotic syndrome	DISVEBC9	Limited	Genetic Variation	[28]
Wilms tumor	DISB6T16	Limited	Genetic Variation	[25]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1) decreases the response to substance of Paclitaxel.	[45]
Capecitabine	DMTS85L	Approved	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1) increases the response to substance of Capecitabine.	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[29]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[32]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[34]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[35]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[36]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[41]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[42]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[43]
Manganese	DMKT129	Investigative	Manganese increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1).	[40]

References

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