Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI6LT46)

• DOT Name: GPI mannosyltransferase 2 (PIGV)
• Synonyms: EC 2.4.1.-; GPI mannosyltransferase II; GPI-MT-II; Phosphatidylinositol-glycan biosynthesis class V protein; PIG-V
• Gene Name: PIGV
• Related Disease:
  Hyperphosphatasia with intellectual disability syndrome 1
  Hirschsprung disease
  Intellectual disability
  Juvenile Paget disease
  Hyperphosphatasia-intellectual disability syndrome
• UniProt ID: PIGV_HUMAN
• EC Number: 2.4.1.-
• Pfam ID: PF04188
• Sequence:
  MWPQDPSRKEVLRFAVSCRILTLMLQALFNAIIPDHHAEAFSPPRLAPSGFVDQLVEGLL
  GGLSHWDAEHFLFIAEHGYLYEHNFAFFPGFPLALLVGTELLRPLRGLLSLRSCLLISVA
  SLNFLFFMLAAVALHDLGCLVLHCPHQSFYAALLFCLSPANVFLAAGYSEALFALLTFSA
  MGQLERGRVWTSVLLFAFATGVRSNGLVSVGFLMHSQCQGFFSSLTMLNPLRQLFKLMAS
  LFLSVFTLGLPFALFQYYAYTQFCLPGSARPIPEPLVQLAVDKGYRIAEGNEPPWCFWDV
  PLIYSYIQDVYWNVGFLKYYELKQVPNFLLAAPVAILVAWATWTYVTTHPWLCLTLGLQR
  SKNNKTLEKPDLGFLSPQVFVYVVHAAVLLLFGGLCMHVQVLTRFLGSSTPIMYWFPAHL
  LQDQEPLLRSLKTVPWKPLAEDSPPGQKVPRNPIMGLLYHWKTCSPVTRYILGYFLTYWL
  LGLLLHCNFLPWT
• Function: Alpha-1,6-mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the second mannose to the glycosylphosphatidylinositol during GPI precursor assembly.
• 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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperphosphatasia with intellectual disability syndrome 1	DISICS2R	Definitive	Autosomal recessive	[1]
Hirschsprung disease	DISUUSM1	Strong	Genetic Variation	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
Juvenile Paget disease	DISNVDB2	Strong	Genetic Variation	[3]
Hyperphosphatasia-intellectual disability syndrome	DISQJ9HK	Supportive	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
D-mannose	DMT6X03	Investigative	GPI mannosyltransferase 2 (PIGV) increases the metabolism of D-mannose.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of GPI mannosyltransferase 2 (PIGV).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GPI mannosyltransferase 2 (PIGV).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GPI mannosyltransferase 2 (PIGV).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of GPI mannosyltransferase 2 (PIGV).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of GPI mannosyltransferase 2 (PIGV).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of GPI mannosyltransferase 2 (PIGV).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of GPI mannosyltransferase 2 (PIGV).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of GPI mannosyltransferase 2 (PIGV).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of GPI mannosyltransferase 2 (PIGV).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of GPI mannosyltransferase 2 (PIGV).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of GPI mannosyltransferase 2 (PIGV).	[13]

References

• [1] Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet. 2010 Oct;42(10):827-9. doi: 10.1038/ng.653. Epub 2010 Aug 29.
• [2] Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome. Eur J Hum Genet. 2014 Jun;22(6):762-7. doi: 10.1038/ejhg.2013.241. Epub 2013 Oct 16.
• [3] Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up.Mol Genet Metab. 2011 Sep-Oct;104(1-2):48-60. doi: 10.1016/j.ymgme.2011.05.014. Epub 2011 May 24.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] 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.
• [14] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [15] PIG-V involved in transferring the second mannose in glycosylphosphatidylinositol. J Biol Chem. 2005 Mar 11;280(10):9489-97. doi: 10.1074/jbc.M413867200. Epub 2004 Dec 28.