Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTQQ7FN)

• DOT Name: Alpha-L-iduronidase (IDUA)
• Synonyms: EC 3.2.1.76
• Gene Name: IDUA
• Related Disease:
  Mucopolysaccharidosis I
  Scheie syndrome
  Hurler syndrome
  Hurler-Scheie syndrome
• UniProt ID: IDUA_HUMAN
• PDB ID: 3W81; 3W82; 4KGJ; 4KGL; 4KH2; 4MJ2; 4MJ4; 4OBR; 4OBS; 6I6R; 6I6X
• EC Number: 3.2.1.76
• Pfam ID: PF01229 ; PF21200
• Sequence:
  MRPLRPRAALLALLASLLAAPPVAPAEAPHLVHVDAARALWPLRRFWRSTGFCPPLPHSQ
  ADQYVLSWDQQLNLAYVGAVPHRGIKQVRTHWLLELVTTRGSTGRGLSYNFTHLDGYLDL
  LRENQLLPGFELMGSASGHFTDFEDKQQVFEWKDLVSSLARRYIGRYGLAHVSKWNFETW
  NEPDHHDFDNVSMTMQGFLNYYDACSEGLRAASPALRLGGPGDSFHTPPRSPLSWGLLRH
  CHDGTNFFTGEAGVRLDYISLHRKGARSSISILEQEKVVAQQIRQLFPKFADTPIYNDEA
  DPLVGWSLPQPWRADVTYAAMVVKVIAQHQNLLLANTTSAFPYALLSNDNAFLSYHPHPF
  AQRTLTARFQVNNTRPPHVQLLRKPVLTAMGLLALLDEEQLWAEVSQAGTVLDSNHTVGV
  LASAHRPQGPADAWRAAVLIYASDDTRAHPNRSVAVTLRLRGVPPGPGLVYVTRYLDNGL
  CSPDGEWRRLGRPVFPTAEQFRRMRAAEDPVAAAPRPLPAGGRLTLRPALRLPSLLLVHV
  CARPEKPPGQVTRLRALPLTQGQLVLVWSDEHVGSKCLWTYEIQFSQDGKAYTPVSRKPS
  TFNLFVFSPDTGAVSGSYRVRALDYWARPGPFSDPVPYLEVPVPRGPPSPGNP
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  CS/DS degradation (R-HSA-2024101)
  MPS I - Hurler syndrome (R-HSA-2206302)
  HS-GAG degradation (R-HSA-2024096)
• BioCyc Pathway: MetaCyc:HS05096-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mucopolysaccharidosis I	DISTS29G	Definitive	Autosomal recessive	[1]
Scheie syndrome	DIS24G0Z	Definitive	Autosomal recessive	[2]
Hurler syndrome	DIS1DPSN	Strong	Autosomal recessive	[3]
Hurler-Scheie syndrome	DIS1YJC5	Strong	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Alpha-L-iduronidase (IDUA).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-L-iduronidase (IDUA).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Alpha-L-iduronidase (IDUA).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Alpha-L-iduronidase (IDUA).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Alpha-L-iduronidase (IDUA).	[8]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Alpha-L-iduronidase (IDUA).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-L-iduronidase (IDUA).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Alpha-L-iduronidase (IDUA).	[8]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Alpha-L-iduronidase (IDUA).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Alpha-L-iduronidase (IDUA).	[11]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Alpha-L-iduronidase (IDUA).	[11]

References

• [1] 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.
• [2] Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients. Hum Mol Genet. 1994 Jun;3(6):861-6. doi: 10.1093/hmg/3.6.861.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. J Mol Biol. 2004 Apr 30;338(3):453-62.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.