Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWA8819)

• DOT Name: GPI transamidase component PIG-T (PIGT)
• Synonyms: Phosphatidylinositol-glycan biosynthesis class T protein
• Gene Name: PIGT
• Related Disease:
  Multiple congenital anomalies-hypotonia-seizures syndrome 3
  Breast cancer
  Breast carcinoma
  Epilepsy
  Hypophosphatasia
  Paroxysmal nocturnal haemoglobinuria
• UniProt ID: PIGT_HUMAN
• PDB ID: 7W72; 7WLD; 8IMX; 8IMY
• Pfam ID: PF04113
• Sequence:
  MAAAMPLALLVLLLLGPGGWCLAEPPRDSLREELVITPLPSGDVAATFQFRTRWDSELQR
  EGVSHYRLFPKALGQLISKYSLRELHLSFTQGFWRTRYWGPPFLQAPSGAELWVWFQDTV
  TDVDKSWKELSNVLSGIFCASLNFIDSTNTVTPTASFKPLGLANDTDHYFLRYAVLPREV
  VCTENLTPWKKLLPCSSKAGLSVLLKADRLFHTSYHSQAVHIRPVCRNARCTSISWELRQ
  TLSVVFDAFITGQGKKDWSLFRMFSRTLTEPCPLASESRVYVDITTYNQDNETLEVHPPP
  TTTYQDVILGTRKTYAIYDLLDTAMINNSRNLNIQLKWKRPPENEAPPVPFLHAQRYVSG
  YGLQKGELSTLLYNTHPYRAFPVLLLDTVPWYLRLYVHTLTITSKGKENKPSYIHYQPAQ
  DRLQPHLLEMLIQLPANSVTKVSIQFERALLKWTEYTPDPNHGFYVSPSVLSALVPSMVA
  AKPVDWEESPLFNSLFPVSDGSNYFVRLYTEPLLVNLPTPDFSMPYNVICLTCTVVAVCY
  GSFYNLLTRTFHIEEPRTGGLAKRLANLIRRARGVPPL
• Function: Component of the GPI transamidase complex. Essential for transfer of GPI to proteins, particularly for formation of carbonyl intermediates.
• KEGG Pathway:
  Glycosylphosphatidylinositol (GPI)-anchor biosynthesis (hsa00563)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Attachment of GPI anchor to uPAR (R-HSA-162791)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple congenital anomalies-hypotonia-seizures syndrome 3	DISPNER0	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Hypophosphatasia	DISCQ0O2	Strong	Genetic Variation	[4]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of GPI transamidase component PIG-T (PIGT).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GPI transamidase component PIG-T (PIGT).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of GPI transamidase component PIG-T (PIGT).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of GPI transamidase component PIG-T (PIGT).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of GPI transamidase component PIG-T (PIGT).	[10]

References

• [1] A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. J Med Genet. 2013 Aug;50(8):521-8. doi: 10.1136/jmedgenet-2013-101654. Epub 2013 May 1.
• [2] Overexpression of glycosylphosphatidylinositol (GPI) transamidase subunits phosphatidylinositol glycan class T and/or GPI anchor attachment 1 induces tumorigenesis and contributes to invasion in human breast cancer.Cancer Res. 2006 Oct 15;66(20):9829-36. doi: 10.1158/0008-5472.CAN-06-0506.
• [3] PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics. Genet Med. 2019 Oct;21(10):2216-2223. doi: 10.1038/s41436-019-0512-3. Epub 2019 Apr 12.
• [4] Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3.Neurogenetics. 2014 Aug;15(3):193-200. doi: 10.1007/s10048-014-0408-y. Epub 2014 Jun 8.
• [5] Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation.J Clin Invest. 2019 Dec 2;129(12):5123-5136. doi: 10.1172/JCI123501.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [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.