Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNAEAZ6)

• DOT Name: N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL)
• Synonyms: EC 3.5.1.89; Phosphatidylinositol-glycan biosynthesis class L protein; PIG-L
• Gene Name: PIGL
• Related Disease:
  CHIME syndrome
  Syndromic intellectual disability
  Hyperphosphatasia-intellectual disability syndrome
• UniProt ID: PIGL_HUMAN
• EC Number: 3.5.1.89
• Pfam ID: PF02585
• Sequence:
  MEAMWLLCVALAVLAWGFLWVWDSSERMKSREQGGRLGAESRTLLVIAHPDDEAMFFAPT
  VLGLARLRHWVYLLCFSAGNYYNQGETRKKELLQSCDVLGIPLSSVMIIDNRDFPDDPGM
  QWDTEHVARVLLQHIEVNGINLVVTFDAGGVSGHSNHIALYAAVRALHSEGKLPKGCSVL
  TLQSVNVLRKYISLLDLPLSLLHTQDVLFVLNSKEVAQAKKAMSCHRSQLLWFRRLYIIF
  SRYMRINSLSFL
• Function: Catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol.
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CHIME syndrome	DIST8B4W	Definitive	Autosomal recessive	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal recessive	[2]
Hyperphosphatasia-intellectual disability syndrome	DISQJ9HK	Supportive	Autosomal recessive	[3]

6 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 N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIGL).	[9]

References

• [1] Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome. Am J Hum Genet. 2012 Apr 6;90(4):685-8. doi: 10.1016/j.ajhg.2012.02.010. Epub 2012 Mar 22.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Mutations in PIGL in a patient with Mabry syndrome. Am J Med Genet A. 2015 Apr;167A(4):777-85. doi: 10.1002/ajmg.a.36987. Epub 2015 Feb 23.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] 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.