Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0IIMI5)

• DOT Name: Phospholipid phosphatase 1 (PLPP1)
• Synonyms: EC 3.1.3.-; EC 3.1.3.106; EC 3.1.3.4; EC 3.6.1.75; Lipid phosphate phosphohydrolase 1; PAP2-alpha; Phosphatidate phosphohydrolase type 2a; Phosphatidic acid phosphatase 2a; PAP-2a; PAP2a
• Gene Name: PLPP1
• UniProt ID: PLPP1_HUMAN
• EC Number: 3.1.3.-; 3.1.3.106; 3.1.3.4; 3.6.1.75
• Pfam ID: PF01569
• Sequence:
  MFDKTRLPYVALDVLCVLLAGLPFAILTSRHTPFQRGVFCNDESIKYPYKEDTIPYALLG
  GIIIPFSIIVIILGETLSVYCNLLHSNSFIRNNYIATIYKAIGTFLFGAAASQSLTDIAK
  YSIGRLRPHFLDVCDPDWSKINCSDGYIEYYICRGNAERVKEGRLSFYSGHSSFSMYCML
  FVALYLQARMKGDWARLLRPTLQFGLVAVSIYVGLSRVSDYKHHWSDVLTGLIQGALVAI
  LVAVYVSDFFKERTSFKERKEEDSHTTLHETPTTGNHYPSNHQP
• Function: Magnesium-independent phospholipid phosphatase of the plasma membrane that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, diacylglycerol pyrophosphate/DGPP, sphingosine 1-phosphate/S1P and ceramide 1-phosphate/C1P. Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound. Through its extracellular phosphatase activity allows both the hydrolysis and the cellular uptake of these bioactive lipid mediators from the milieu, regulating signal transduction in different cellular processes. It is for instance essential for the extracellular hydrolysis of S1P and subsequent conversion into intracellular S1P. Involved in the regulation of inflammation, platelets activation, cell proliferation and migration among other processes. May also have an intracellular activity to regulate phospholipid-mediated signaling pathways.
• Tissue Specificity: Widely expressed with highest expression found in prostate . Found to be down-regulated in colon adenocarcinomas .; [Isoform 1]: Predominant in kidney, lung, placenta and liver.; [Isoform 2]: Predominant in heart and pancreas.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Phospholipase D sig.ling pathway (hsa04072)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Fat digestion and absorption (hsa04975)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway: Sphingolipid metabolism (R-HSA-428157)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Phospholipid phosphatase 1 (PLPP1) affects the response to substance of Methotrexate.	[13]
Irinotecan	DMP6SC2	Approved	Phospholipid phosphatase 1 (PLPP1) decreases the response to substance of Irinotecan.	[14]
Paclitaxel	DMLB81S	Approved	Phospholipid phosphatase 1 (PLPP1) decreases the response to substance of Paclitaxel.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Phospholipid phosphatase 1 (PLPP1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phospholipid phosphatase 1 (PLPP1).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phospholipid phosphatase 1 (PLPP1).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Phospholipid phosphatase 1 (PLPP1).	[4]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Phospholipid phosphatase 1 (PLPP1).	[4]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Phospholipid phosphatase 1 (PLPP1).	[5]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Phospholipid phosphatase 1 (PLPP1).	[6]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Phospholipid phosphatase 1 (PLPP1).	[7]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Phospholipid phosphatase 1 (PLPP1).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phospholipid phosphatase 1 (PLPP1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phospholipid phosphatase 1 (PLPP1).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Phospholipid phosphatase 1 (PLPP1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phospholipid phosphatase 1 (PLPP1).	[11]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [4] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [5] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [6] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [7] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [8] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [13] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [14] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.