Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY98K40)

• DOT Name: GPI mannosyltransferase 1 (PIGM)
• Synonyms: EC 2.4.1.-; GPI mannosyltransferase I; GPI-MT-I; Phosphatidylinositol-glycan biosynthesis class M protein; PIG-M
• Gene Name: PIGM
• Related Disease:
  Epilepsy
  Megalencephaly
  Paroxysmal nocturnal haemoglobinuria
  Primary CD59 deficiency
  Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency
• UniProt ID: PIGM_HUMAN
• EC Number: 2.4.1.-
• Pfam ID: PF05007
• Sequence:
  MGSTKHWGEWLLNLKVAPAGVFGVAFLARVALVFYGVFQDRTLHVRYTDIDYQVFTDAAR
  FVTEGRSPYLRATYRYTPLLGWLLTPNIYLSELFGKFLFISCDLLTAFLLYRLLLLKGLG
  RRQACGYCVFWLLNPLPMAVSSRGNADSIVASLVLMVLYLIKKRLVACAAVFYGFAVHMK
  IYPVTYILPITLHLLPDRDNDKSLRQFRYTFQACLYELLKRLCNRAVLLFVAVAGLTFFA
  LSFGFYYEYGWEFLEHTYFYHLTRRDIRHNFSPYFYMLYLTAESKWSFSLGIAAFLPQLI
  LLSAVSFAYYRDLVFCCFLHTSIFVTFNKVCTSQYFLWYLCLLPLVMPLVRMPWKRAVVL
  LMLWFIGQAMWLAPAYVLEFQGKNTFLFIWLAGLFFLLINCSILIQIISHYKEEPLTERI
  KYD
• Function: Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the first alpha-1,4-mannose to GlcN-acyl-PI 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
Epilepsy	DISBB28L	Strong	Genetic Variation	[1]
Megalencephaly	DISYW5SV	Strong	Biomarker	[2]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Genetic Variation	[3]
Primary CD59 deficiency	DISQH167	Strong	Genetic Variation	[3]
Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency	DISO56WE	Moderate	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of GPI mannosyltransferase 1 (PIGM).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GPI mannosyltransferase 1 (PIGM).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GPI mannosyltransferase 1 (PIGM).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GPI mannosyltransferase 1 (PIGM).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GPI mannosyltransferase 1 (PIGM).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GPI mannosyltransferase 1 (PIGM).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of GPI mannosyltransferase 1 (PIGM).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of GPI mannosyltransferase 1 (PIGM).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of GPI mannosyltransferase 1 (PIGM).	[12]

References

• [1] Targeted therapy for inherited GPI deficiency.N Engl J Med. 2007 Apr 19;356(16):1641-7. doi: 10.1056/NEJMoa063369.
• [2] Cerebral and portal vein thrombosis, macrocephaly and atypical absence seizures in Glycosylphosphatidyl inositol deficiency due to a PIGM promoter mutation. Mol Genet Metab. 2019 Sep-Oct;128(1-2):151-161. doi: 10.1016/j.ymgme.2019.08.003. Epub 2019 Aug 14.
• [3] Heterogeneity in the molecular pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) syndromes and expansion mechanism of a PNH clone.Int J Hematol. 2006 Aug;84(2):97-103. doi: 10.1532/IJH97.06083.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.