Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGYAH4X)

• DOT Name: Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP)
• Synonyms: Down syndrome critical region protein 5; Down syndrome critical region protein C; Phosphatidylinositol-glycan biosynthesis class P protein; PIG-P
• Gene Name: PIGP
• Related Disease:
  Developmental and epileptic encephalopathy, 55
  Epileptic encephalopathy
  Infantile epileptic-dyskinetic encephalopathy
  Prostate cancer
  Prostate neoplasm
  Intellectual disability
  Infantile spasm
• UniProt ID: PIGP_HUMAN
• Pfam ID: PF08510
• Sequence:
  MVPRSTSLTLIVFLFHRLSKAPGKMVENSPSPLPERAIYGFVLFLSSQFGFILYLVWAFI
  PESWLNSLGLTYWPQKYWAVALPVYLLIAIVIGYVLLFGINMMSTSPLDSIHTITDNYAK
  NQQQKKYQEEAIPALRDISISEVNQMFFLAAKELYTKN
• Function: Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Glycosylphosphatidylinositol (GPI)-anchor biosynthesis (hsa00563)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of glycosylphosphatidylinositol (GPI) (R-HSA-162710)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 55	DISADPHL	Strong	Autosomal recessive	[1]
Epileptic encephalopathy	DISZOCA3	Strong	GermlineCausalMutation	[2]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	moderate	Biomarker	[1]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[2]

8 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 N-acetylglucosaminyltransferase subunit P (PIGP).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP).	[8]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphatidylinositol N-acetylglucosaminyltransferase subunit P (PIGP).	[11]

References

• [1] Biallelic mutations in PIGP cause developmental and epileptic encephalopathy. Ann Clin Transl Neurol. 2019 Apr 11;6(5):968-973. doi: 10.1002/acn3.768. eCollection 2019 May.
• [2] Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. Hum Mol Genet. 2017 May 1;26(9):1706-1715. doi: 10.1093/hmg/ddx077.
• [3] The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5(4):e1195. doi: 10.1038/cddis.2014.157.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.