Details of Drug Off-Target (DOT)

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

• DOT Name: Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6)
• Synonyms: EC 3.1.3.-; EC 3.6.1.-; EC 3.6.1.68; Lipid phosphatase-related protein-B; LPRP-B; PA-PSP; Phosphatidic acid phosphatase type 2 domain-containing protein 2; PPAP2 domain-containing protein 2; Phospholipid phosphatase 6; Presqualene diphosphate phosphatase; Type 1 polyisoprenoid diphosphate phosphatase
• Gene Name: PLPP6
• UniProt ID: PLPP6_HUMAN
• EC Number: 3.1.3.-; 3.6.1.-; 3.6.1.68
• Pfam ID: PF01569
• Sequence:
  MPSPRRSMEGRPLGVSASSSSSSPGSPAHGGGGGGSRFEFQSLLSSRATAVDPTCARLRA
  SESPVHRRGSFPLAAAGPSQSPAPPLPEEDRMDLNPSFLGIALRSLLAIDLWLSKKLGVC
  AGESSSWGSVRPLMKLLEISGHGIPWLLGTLYCLCRSDSWAGREVLMNLLFALLLDLLLV
  ALIKGLVRRRRPAHNQMDMFVTLSVDKYSFPSGHATRAALMSRFILNHLVLAIPLRVLVV
  LWAFVLGLSRVMLGRHNVTDVAFGFFLGYMQYSIVDYCWLSPHNAPVLFLLWSQR
• Function: Magnesium-independent polyisoprenoid diphosphatase that catalyzes the sequential dephosphorylation of presqualene, farnesyl, geranyl and geranylgeranyl diphosphates. Functions in the innate immune response through the dephosphorylation of presqualene diphosphate which acts as a potent inhibitor of the signaling pathways contributing to polymorphonuclear neutrophils activation. May regulate the biosynthesis of cholesterol and related sterols by dephosphorylating presqualene and farnesyl diphosphate, two key intermediates in this biosynthetic pathway. May also play a role in protein prenylation by acting on farnesyl diphosphate and its derivative geranylgeranyl diphosphate, two precursors for the addition of isoprenoid anchors to membrane proteins. Has a lower activity towards phosphatidic acid (PA), but through phosphatidic acid dephosphorylation may participate in the biosynthesis of phospholipids and triacylglycerols. May also act on ceramide-1-P, lysophosphatidic acid (LPA) and sphing-4-enine 1-phosphate/sphingosine-1-phosphate.
• Tissue Specificity: Widely expressed. Expressed in most organs, in particular gastrointestinal organs, spleen, placenta, kidney, thymus and brain.
• Reactome Pathway: Cholesterol biosynthesis (R-HSA-191273)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[2]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[3]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[10]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6 (PLPP6).	[6]

References

• [1] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [2] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [3] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [4] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [5] 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.
• [6] 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.
• [7] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.