Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCC4CEN)

• DOT Name: GPI transamidase component PIG-S (PIGS)
• Synonyms: Phosphatidylinositol-glycan biosynthesis class S protein
• Gene Name: PIGS
• Related Disease:
  Advanced cancer
  Fetal akinesia deformation sequence 1
  Glycosylphosphatidylinositol biosynthesis defect 18
  Hepatocellular carcinoma
• UniProt ID: PIGS_HUMAN
• PDB ID: 7W72; 7WLD; 8IMX; 8IMY
• Pfam ID: PF10510
• Sequence:
  MAAAGAAATHLEVARGKRAALFFAAVAIVLGLPLWWKTTETYRASLPYSQISGLNALQLR
  LMVPVTVVFTRESVPLDDQEKLPFTVVHEREIPLKYKMKIKCRFQKAYRRALDHEEEALS
  SGSVQEAEAMLDEPQEQAEGSLTVYVISEHSSLLPQDMMSYIGPKRTAVVRGIMHREAFN
  IIGRRIVQVAQAMSLTEDVLAAALADHLPEDKWSAEKRRPLKSSLGYEITFSLLNPDPKS
  HDVYWDIEGAVRRYVQPFLNALGAAGNFSVDSQILYYAMLGVNPRFDSASSSYYLDMHSL
  PHVINPVESRLGSSAASLYPVLNFLLYVPELAHSPLYIQDKDGAPVATNAFHSPRWGGIM
  VYNVDSKTYNASVLPVRVEVDMVRVMEVFLAQLRLLFGIAQPQLPPKCLLSGPTSEGLMT
  WELDRLLWARSVENLATATTTLTSLAQLLGKISNIVIKDDVASEVYKAVAAVQKSAEELA
  SGHLASAFVASQEAVTSSELAFFDPSLLHLLYFPDDQKFAIYIPLFLPMAVPILLSLVKI
  FLETRKSWRKPEKTD
• Function: Component of the GPI transamidase complex. Essential for transfer of GPI to proteins, particularly for formation of carbonyl intermediates.
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Fetal akinesia deformation sequence 1	DISKDI9L	Strong	Genetic Variation	[2]
Glycosylphosphatidylinositol biosynthesis defect 18	DISG4FE5	Strong	Autosomal recessive	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]

5 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 transamidase component PIG-S (PIGS).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GPI transamidase component PIG-S (PIGS).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GPI transamidase component PIG-S (PIGS).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GPI transamidase component PIG-S (PIGS).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GPI transamidase component PIG-S (PIGS).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of GPI transamidase component PIG-S (PIGS).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of GPI transamidase component PIG-S (PIGS).	[9]

References

• [1] A method to generate genetically defined tumors in pigs.Methods Enzymol. 2008;439:39-51. doi: 10.1016/S0076-6879(07)00404-1.
• [2] Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy. Am J Hum Genet. 2018 Oct 4;103(4):602-611. doi: 10.1016/j.ajhg.2018.08.014. Epub 2018 Sep 27.
• [3] High miR-139-3p expression predicts a better prognosis for hepatocellular carcinoma: a pooled analysis.J Int Med Res. 2019 Jan;47(1):383-390. doi: 10.1177/0300060518802727. Epub 2018 Nov 5.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] 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.
• [10] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.