Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBOWTC5)

• DOT Name: Phospholipid phosphatase-related protein type 4 (PLPPR4)
• Synonyms: Brain-specific phosphatidic acid phosphatase-like protein 1; Inactive 2-lysophosphatidate phosphatase PLPPR4; Lipid phosphate phosphatase-related protein type 4; Plasticity-related gene 1 protein; PRG-1
• Gene Name: PLPPR4
• Related Disease:
  Fatty liver disease
  Non-alcoholic fatty liver disease
  Endometrial carcinoma
  Mental disorder
  Periodontal disease
  Periodontitis
• UniProt ID: PLPR4_HUMAN
• Pfam ID: PF01569
• Sequence:
  MQRAGSSGGRGECDISGAGRLGLEEAARLSCAVHTSPGGGRRPGQAAGMSAKERPKGKVI
  KDSVTLLPCFYFVELPILASSVVSLYFLELTDVFKPVHSGFSCYDRSLSMPYIEPTQEAI
  PFLMLLSLAFAGPAITIMVGEGILYCCLSKRRNGVGLEPNINAGGCNFNSFLRRAVRFVG
  VHVFGLCSTALITDIIQLSTGYQAPYFLTVCKPNYTSLNVSCKENSYIVEDICSGSDLTV
  INSGRKSFPSQHATLAAFAAVYVSMYFNSTLTDSSKLLKPLLVFTFIICGIICGLTRITQ
  YKNHPVDVYCGFLIGGGIALYLGLYAVGNFLPSDESMFQHRDALRSLTDLNQDPNRLLSA
  KNGSSSDGIAHTEGILNRNHRDASSLTNLKRANADVEIITPRSPMGKENMVTFSNTLPRA
  NTPSVEDPVRRNASIHASMDSARSKQLLTQWKNKNESRKLSLQVIEPEPGQSPPRSIEMR
  SSSEPSRVGVNGDHHGPGNQYLKIQPGAVPGCNNSMPGGPRVSIQSRPGSSQLVHIPEET
  QENISTSPKSSSARAKWLKAAEKTVACNRSNSQPRIMQVIAMSKQQGVLQSSPKNTEGST
  VSCTGSIRYKTLTDHEPSGIVRVEAHPENNRPIIQIPSTEGEGSGSWKWKAPEKGSLRQT
  YELNDLNRDSESCESLKDSFGSGDRKRSNIDSNEHHHHGITTIRVTPVEGSEIGSETLSI
  SSSRDSTLRRKGNIILIPERSNSPENTRNIFYKGTSPTRAYKD
• Function: Postsynaptic density membrane protein that indirectly regulates glutamatergic synaptic transmission through lysophosphatidic acid (LPA)-mediated signaling pathways. Binds lysophosphatidic acid (LPA) and mediates its internalization into cells. Could act as receptor or a transporter of this lipid at the post-synaptic membrane. Modulates lysophosphatidic acid (LPA) activity in neuron axonal outgrowth during development by attenuating phospholipid-induced axon collapse.
• Tissue Specificity: Expressed by glutamatergic neurons (at protein level).
• Reactome Pathway: Lysosphingolipid and LPA receptors (R-HSA-419408)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[2]
Endometrial carcinoma	DISXR5CY	Limited	Genetic Variation	[3]
Mental disorder	DIS3J5R8	Limited	Biomarker	[4]
Periodontal disease	DISJQHVN	Limited	Biomarker	[5]
Periodontitis	DISI9JOI	Limited	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[9]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[10]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phospholipid phosphatase-related protein type 4 (PLPPR4).	[14]

References

• [1] Impact of genetic polymorphisms associated with nonalcoholic fatty liver disease on HIV-infected individuals.AIDS. 2015 Sep 24;29(15):1927-35. doi: 10.1097/QAD.0000000000000799.
• [2] Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease.Hepatology. 2013 Feb;57(2):590-600. doi: 10.1002/hep.26184.
• [3] Identification of nine new susceptibility loci for endometrial cancer.Nat Commun. 2018 Aug 9;9(1):3166. doi: 10.1038/s41467-018-05427-7.
• [4] Altered synaptic phospholipid signaling in PRG-1 deficient mice induces exploratory behavior and motor hyperactivity resembling psychiatric disorders.Behav Brain Res. 2018 Jan 15;336:1-7. doi: 10.1016/j.bbr.2017.08.032. Epub 2017 Aug 24.
• [5] Porphyromonas gingivalis Tyrosine Phosphatase Php1 Promotes Community Development and Pathogenicity.mBio. 2019 Sep 24;10(5):e02004-19. doi: 10.1128/mBio.02004-19.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] 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.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.