Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1WQ55V)

• DOT Name: GPI inositol-deacylase (PGAP1)
• Synonyms: EC 3.1.-.-; Post-GPI attachment to proteins factor 1; hPGAP1
• Gene Name: PGAP1
• Related Disease:
  Congenital disorder of glycosylation
  Congenital factor XII deficiency
  Intellectual disability
  Intellectual disability, autosomal recessive 42
  Paroxysmal nocturnal haemoglobinuria
  Autosomal recessive non-syndromic intellectual disability
  Autosomal recessive spastic paraplegia type 67
• UniProt ID: PGAP1_HUMAN
• EC Number: 3.1.-.-
• Pfam ID: PF07819
• Sequence:
  MFLHSVNLWNLAFYVFMVFLATLGLWDVFFGFEENKCSMSYMFEYPEYQKIELPKKLAKR
  YPAYELYLYGEGSYAEEHKILPLTGIPVLFLPGNAGSYKQVRSIGSIALRKAEDIDFKYH
  FDFFSVNFNEELVALYGGSLQKQTKFVHECIKTILKLYKGQEFAPKSVAIIGHSMGGLVA
  RALLTLKNFKHDLINLLITQATPHVAPVMPLDRFITDFYTTVNNYWILNARHINLTTLSV
  AGGFRDYQVRSGLTFLPKLSHHTSALSVVSSAVPKTWVSTDHLSIVWCKQLQLTTVRAFF
  DLIDADTKQITQNSKKKLSVLYHHFIRHPSKHFEENPAIISDLTGTSMWVLVKVSKWTYV
  AYNESEKIYFTFPLENHRKIYTHVYCQSTMLDTNSWIFACINSTSMCLQGVDLSWKAELL
  PTIKYLTLRLQDYPSLSHLVVYVPSVRGSKFVVDCEFFKKEKRYIQLPVTHLFSFGLSSR
  KVVLNTNGLYYNLELLNFGQIYQAFKINVVSKCSAVKEEITSIYRLHIPWSYEDSLTIAQ
  APSSTEISLKLHIAQPENNTHVALFKMYTSSDCRYEVTVKTSFSQILGQVVRFHGGALPA
  YVVSNILLAYRGQLYSLFSTGCCLEYATMLDKEAKPYKVDPFVIIIKFLLGYKWFKELWD
  VLLLPELDAVILTCQSMCFPLISLILFLFGTCTAYWSGLLSSASVRLLSSLWLALKRPSE
  LPKDIKMISPDLPFLTIVLIIVSWTTCGALAILLSYLYYVFKVVHLQASLTTFKNSQPVN
  PKHSRRSEKKSNHHKDSSIHHLRLSANDAEDSLRMHSTVINLLTWIVLLSMPSLIYWLKN
  LRYYFKLNPDPCKPLAFILIPTMAILGNTYTVSIKSSKLLKTTSQFPLPLAVGVIAFGSA
  HLYRLPCFVFIPLLLHALCNFM
• Function: Involved in inositol deacylation of GPI-anchored proteins. GPI inositol deacylation may important for efficient transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi.
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[1]
Congenital factor XII deficiency	DISN4DF6	Strong	Genetic Variation	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Intellectual disability, autosomal recessive 42	DIS4V6PK	Strong	Autosomal recessive	[2]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Altered Expression	[3]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[4]
Autosomal recessive spastic paraplegia type 67	DISUPBQE	Supportive	Autosomal recessive	[5]

15 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 GPI inositol-deacylase (PGAP1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GPI inositol-deacylase (PGAP1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GPI inositol-deacylase (PGAP1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GPI inositol-deacylase (PGAP1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of GPI inositol-deacylase (PGAP1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of GPI inositol-deacylase (PGAP1).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of GPI inositol-deacylase (PGAP1).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of GPI inositol-deacylase (PGAP1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of GPI inositol-deacylase (PGAP1).	[14]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of GPI inositol-deacylase (PGAP1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of GPI inositol-deacylase (PGAP1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of GPI inositol-deacylase (PGAP1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GPI inositol-deacylase (PGAP1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of GPI inositol-deacylase (PGAP1).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of GPI inositol-deacylase (PGAP1).	[20]

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 decreases the methylation of GPI inositol-deacylase (PGAP1).	[17]

References

• [1] Cerebral visual impairment and intellectual disability caused by PGAP1 variants.Eur J Hum Genet. 2015 Dec;23(12):1689-93. doi: 10.1038/ejhg.2015.42. Epub 2015 Mar 25.
• [2] oto is a homeotic locus with a role in anteroposterior development that is partially redundant with Lim1. Development. 1999 Nov;126(22):5085-95. doi: 10.1242/dev.126.22.5085.
• [3] The Monoclonal Anti-CD157 Antibody Clone SY11B5, Used for High Sensitivity Detection of PNH Clones on WBCs, Fails to Detect a Common Polymorphic Variant Encoded by BST-1.Cytometry B Clin Cytom. 2018 Jul;94(4):652-659. doi: 10.1002/cyto.b.21625. Epub 2018 Feb 9.
• [4] Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy. PLoS Genet. 2014 May 1;10(5):e1004320. doi: 10.1371/journal.pgen.1004320. eCollection 2014 May.
• [5] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.