Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT9SMTF)

• DOT Name: Phosphatidylinositol-glycan biosynthesis class W protein (PIGW)
• Synonyms: PIG-W; EC 2.3.-.-
• Gene Name: PIGW
• Related Disease:
  Pneumonia
  West syndrome
  Congenital diaphragmatic hernia
  Epilepsy
  Hyperphosphatasia with intellectual disability syndrome 5
  Intellectual disability
  Nervous system disease
  Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency
  Hyperphosphatasia-intellectual disability syndrome
• UniProt ID: PIGW_HUMAN
• EC Number: 2.3.-.-
• Pfam ID: PF06423
• Sequence:
  MSEKQMKEAFVSNLNGTTVLEITQGLCFPAFCILCRGFLIIFSQYLCSFSPTWKTRFLTD
  FVVLIVPMVATLTIWASFILLELLGVIIFGAGLLYQIYRRRTCYARLPFLKILEKFLNIS
  LESEYNPAISCFRVITSAFTAIAILAVDFPLFPRRFAKTELYGTGAMDFGVGGFVFGSAM
  VCLEVRRRKYMEGSKLHYFTNSLYSVWPLVFLGIGRLAIIKSIGYQEHLTEYGVHWNFFF
  TIIVVKLITPLLLIIFPLNKSWIIALGITVLYQLALDFTSLKRLILYGTDGSGTRVGLLN
  ANREGIISTLGYVAIHMAGVQTGLYMHKNRSHIKDLIKVACFLLLAAISLFISLYVVQVN
  VEAVSRRMANLAFCIWIVASSLILLSSLLLGDIILSFAKFLIKGALVPCSWKLIQSPVTN
  KKHSESLVPEAERMEPSLCLITALNRKQLIFFLLSNITTGLINLMVDTLHSSTLWALFVV
  NLYMFSNCLIVYVLYLQDKTVQFW
• Function: Required for the transport of GPI-anchored proteins to the plasma membrane. Probable acetyltransferase, which acetylates the inositol ring of phosphatidylinositol during biosynthesis of GPI-anchor. Acetylation during GPI-anchor biosynthesis is not essential for the subsequent mannosylation and is usually removed soon after the attachment of GPIs to proteins.
• 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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pneumonia	DIS8EF3M	Definitive	Biomarker	[1]
West syndrome	DISLIAU9	Definitive	Genetic Variation	[2]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Hyperphosphatasia with intellectual disability syndrome 5	DIST5EI1	Strong	Autosomal recessive	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[5]
Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency	DISO56WE	Supportive	Autosomal recessive	[6]
Hyperphosphatasia-intellectual disability syndrome	DISQJ9HK	Supportive	Autosomal recessive	[4]

18 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-glycan biosynthesis class W protein (PIGW).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[15]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[21]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Phosphatidylinositol-glycan biosynthesis class W protein (PIGW).	[22]

References

• [1] APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia.Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01715-18. doi: 10.1128/AAC.01715-18. Print 2019 Feb.
• [2] Use of Flow Cytometry for Diagnosis of Epilepsy Associated With Homozygous PIGW Variants.Pediatr Neurol. 2018 Aug;85:67-70. doi: 10.1016/j.pediatrneurol.2018.05.010. Epub 2018 Jun 5.
• [3] Congenital diaphragmatic hernia may be associated with 17q12 microdeletion syndrome.Am J Med Genet A. 2015 Jan;167A(1):250-3. doi: 10.1002/ajmg.a.36840. Epub 2014 Nov 25.
• [4] Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation syndrome. J Med Genet. 2014 Mar;51(3):203-7. doi: 10.1136/jmedgenet-2013-102156. Epub 2013 Dec 23.
• [5] Mutations in the PIGW gene associated with hyperphosphatasia and mental retardation syndrome: a case report.BMC Pediatr. 2019 Feb 27;19(1):68. doi: 10.1186/s12887-019-1440-8.
• [6] A novel mutation in PIGW causes glycosylphosphatidylinositol deficiency without hyperphosphatasia. Am J Med Genet A. 2016 Dec;170(12):3319-3322. doi: 10.1002/ajmg.a.37950. Epub 2016 Sep 14.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [16] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] 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.