Details of Drug Off-Target (DOT)

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

• DOT Name: Phosphatidylinositol-glycan-specific phospholipase D (GPLD1)
• Synonyms: PI-G PLD; EC 3.1.4.50; Glycoprotein phospholipase D; Glycosyl-phosphatidylinositol-specific phospholipase D; GPI-PLD; GPI-specific phospholipase D
• Gene Name: GPLD1
• Related Disease:
  Ovarian neoplasm
  Advanced cancer
  Brain infarction
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Coronary atherosclerosis
  Liver failure
  Melanoma
  Myocardial infarction
  Myocardial ischemia
  Osteoporosis
  Prostate cancer
  Prostate carcinoma
  Tangier disease
  Thyroid gland carcinoma
  Neoplasm
  Autosomal dominant polycystic liver disease
  Rheumatoid arthritis
  Small lymphocytic lymphoma
  Undifferentiated carcinoma
• UniProt ID: PHLD_HUMAN
• EC Number: 3.1.4.50
• Pfam ID: PF01839 ; PF00882
• Sequence:
  MSAFRLWPGLLIMLGSLCHRGSPCGLSTHVEIGHRALEFLQLHNGRVNYRELLLEHQDAY
  QAGIVFPDCFYPSICKGGKFHDVSESTHWTPFLNASVHYIRENYPLPWEKDTEKLVAFLF
  GITSHMAADVSWHSLGLEQGFLRTMGAIDFHGSYSEAHSAGDFGGDVLSQFEFNFNYLAR
  RWYVPVKDLLGIYEKLYGRKVITENVIVDCSHIQFLEMYGEMLAVSKLYPTYSTKSPFLV
  EQFQEYFLGGLDDMAFWSTNIYHLTSFMLENGTSDCNLPENPLFIACGGQQNHTQGSKMQ
  KNDFHRNLTTSLTESVDRNINYTERGVFFSVNSWTPDSMSFIYKALERNIRTMFIGGSQL
  SQKHVSSPLASYFLSFPYARLGWAMTSADLNQDGHGDLVVGAPGYSRPGHIHIGRVYLIY
  GNDLGLPPVDLDLDKEAHRILEGFQPSGRFGSALAVLDFNVDGVPDLAVGAPSVGSEQLT
  YKGAVYVYFGSKQGGMSSSPNITISCQDIYCNLGWTLLAADVNGDSEPDLVIGSPFAPGG
  GKQKGIVAAFYSGPSLSDKEKLNVEAANWTVRGEEDFSWFGYSLHGVTVDNRTLLLVGSP
  TWKNASRLGHLLHIRDEKKSLGRVYGYFPPNGQSWFTISGDKAMGKLGTSLSSGHVLMNG
  TLKQVLLVGAPTYDDVSKVAFLTVTLHQGGATRMYALTSDAQPLLLSTFSGDRRFSRFGG
  VLHLSDLDDDGLDEIIMAAPLRIADVTSGLIGGEDGRVYVYNGKETTLGDMTGKCKSWIT
  PCPEEKAQYVLISPEASSRFGSSLITVRSKAKNQVVIAAGRSSLGARLSGALHVYSLGSD
• Function: This protein hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans (GPI-anchor) thus releasing these proteins from the membrane.
• KEGG Pathway:
  Glycosylphosphatidylinositol (GPI)-anchor biosynthesis (hsa00563)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ovarian neoplasm	DISEAFTY	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Brain infarction	DISPPGYK	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[3]
Liver failure	DISLGEL6	Strong	Biomarker	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[7]
Myocardial infarction	DIS655KI	Strong	Biomarker	[3]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[3]
Osteoporosis	DISF2JE0	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[9]
Tangier disease	DIS57P0M	Strong	Biomarker	[10]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Autosomal dominant polycystic liver disease	DISJS005	Disputed	Genetic Variation	[12]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[13]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[14]
Undifferentiated carcinoma	DISIAZST	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[18]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[24]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylinositol-glycan-specific phospholipase D (GPLD1).	[20]

References

• [1] GPI-specific phospholipase D mRNA expression in tumor cells of different malignancy.Clin Exp Metastasis. 2002;19(4):291-9. doi: 10.1023/a:1015545407700.
• [2] Phospholipase D inhibitors reduce human prostate cancer cell proliferation and colony formation.Br J Cancer. 2018 Jan;118(2):189-199. doi: 10.1038/bjc.2017.391. Epub 2017 Nov 14.
• [3] Enzymatic Activity Is Not Required for Phospholipase D Mediated TNF- Regulation and Myocardial Healing.Front Physiol. 2018 Nov 29;9:1698. doi: 10.3389/fphys.2018.01698. eCollection 2018.
• [4] PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases.PLoS One. 2016 Nov 16;11(11):e0166553. doi: 10.1371/journal.pone.0166553. eCollection 2016.
• [5] Phospholipase D activation mediates growth and migration of colon cancer cells interacting with cancer-associated fibroblasts.Cell Mol Biol (Noisy-le-grand). 2018 Nov 30;64(14):84-88.
• [6] Polycystic liver disease: Hepatic venous outflow obstruction lesions of the noncystic parenchyma have major consequences.Hepatology. 2018 Aug;68(2):652-662. doi: 10.1002/hep.29582. Epub 2018 Jul 11.
• [7] PLD-repair in human melanoma xenografts following single dose and fractionated irradiation.Br J Cancer. 1990 Jun;61(6):856-60. doi: 10.1038/bjc.1990.191.
• [8] Does primary lactase deficiency reduce bone mineral density in postmenopausal women? A systematic review and meta-analysis.Osteoporos Int. 2018 Nov;29(11):2399-2407. doi: 10.1007/s00198-018-4635-1. Epub 2018 Jul 16.
• [9] Elevated phospholipase D activity in androgen-insensitive prostate cancer cells promotes both survival and metastatic phenotypes.Cancer Lett. 2018 Jun 1;423:28-35. doi: 10.1016/j.canlet.2018.03.006. Epub 2018 Mar 8.
• [10] Cellular cholesterol efflux is modulated by phospholipid-derived signaling molecules in familial HDL deficiency/Tangier disease fibroblasts.J Lipid Res. 2001 Feb;42(2):249-57.
• [11] Tumor cell-secreted PLD increases tumor stemness by senescence-mediated communication with microenvironment.Oncogene. 2019 Feb;38(8):1309-1323. doi: 10.1038/s41388-018-0527-2. Epub 2018 Oct 10.
• [12] Adenylyl cyclase 5 links changes in calcium homeostasis to cAMP-dependent cyst growth in polycystic liver disease.J Hepatol. 2017 Mar;66(3):571-580. doi: 10.1016/j.jhep.2016.10.032. Epub 2016 Nov 5.
• [13] IL-15 promotes osteoclastogenesis via the PLD pathway in rheumatoid arthritis.Immunol Lett. 2011 Sep 30;139(1-2):42-51. doi: 10.1016/j.imlet.2011.04.013. Epub 2011 May 19.
• [14] Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer.J Control Release. 2017 Sep 10;261:287-296. doi: 10.1016/j.jconrel.2017.07.010. Epub 2017 Jul 9.
• [15] Modulatory role of phospholipase D in the activation of signal transducer and activator of transcription (STAT)-3 by thyroid oncogenic kinase RET/PTC.BMC Cancer. 2008 May 23;8:144. doi: 10.1186/1471-2407-8-144.
• [16] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] 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.
• [19] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] 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.