Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT76ZSX5)

• DOT Name: Protein disulfide-isomerase A5 (PDIA5)
• Synonyms: EC 5.3.4.1; Protein disulfide isomerase-related protein
• Gene Name: PDIA5
• Related Disease:
  Insulinoma
  Mucopolysaccharidosis
  Angle-closure glaucoma
  Glaucoma/ocular hypertension
  Primary angle-closure glaucoma
  High blood pressure
  Type-1/2 diabetes
• UniProt ID: PDIA5_HUMAN
• PDB ID: 4I6X
• EC Number: 5.3.4.1
• Pfam ID: PF00085
• Sequence:
  MARAGPAWLLLAIWVVLPSWLSSAKVSSLIERISDPKDLKKLLRTRNNVLVLYSKSEVAA
  ENHLRLLSTVAQAVKGQGTICWVDCGDAESRKLCKKMKVDLSPKDKKVELFHYQDGAFHT
  EYNRAVTFKSIVAFLKDPKGPPLWEEDPGAKDVVHLDSEKDFRRLLKKEEKPLLIMFYAP
  WCSMCKRMMPHFQKAATQLRGHAVLAGMNVYSSEFENIKEEYSVRGFPTICYFEKGRFLF
  QYDNYGSTAEDIVEWLKNPQPPQPQVPETPWADEGGSVYHLTDEDFDQFVKEHSSVLVMF
  HAPWCGHCKKMKPEFEKAAEALHGEADSSGVLAAVDATVNKALAERFHISEFPTLKYFKN
  GEKYAVPVLRTKKKFLEWMQNPEAPPPPEPTWEEQQTSVLHLVGDNFRETLKKKKHTLVM
  FYAPWCPHCKKVIPHFTATADAFKDDRKIACAAVDCVKDKNQDLCQQEAVKGYPTFHYYH
  YGKFAEKYDSDRTELGFTNYIRALREGDHERLGKKKEEL
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Insulinoma	DISIU1JS	Strong	Altered Expression	[1]
Mucopolysaccharidosis	DISB083T	Strong	Altered Expression	[2]
Angle-closure glaucoma	DISZ95KY	Disputed	Genetic Variation	[3]
Glaucoma/ocular hypertension	DISLBXBY	Disputed	Genetic Variation	[3]
Primary angle-closure glaucoma	DISX8UKZ	Disputed	Genetic Variation	[3]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[4]

19 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 Protein disulfide-isomerase A5 (PDIA5).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein disulfide-isomerase A5 (PDIA5).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein disulfide-isomerase A5 (PDIA5).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein disulfide-isomerase A5 (PDIA5).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein disulfide-isomerase A5 (PDIA5).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein disulfide-isomerase A5 (PDIA5).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Protein disulfide-isomerase A5 (PDIA5).	[6]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[6]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[6]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[6]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Protein disulfide-isomerase A5 (PDIA5).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein disulfide-isomerase A5 (PDIA5).	[14]

References

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• [2] Unfolded protein response is not activated in the mucopolysaccharidoses but protein disulfide isomerase 5 is deregulated.J Inherit Metab Dis. 2012 May;35(3):479-93. doi: 10.1007/s10545-011-9403-8. Epub 2011 Oct 15.
• [3] Association of a polymorphism in the BIRC6 gene with pseudoexfoliative glaucoma.PLoS One. 2014 Aug 13;9(8):e105023. doi: 10.1371/journal.pone.0105023. eCollection 2014.
• [4] Identification of six polymorphisms as novel susceptibility loci for ischemic or hemorrhagic stroke by exome-wide association studies.Int J Mol Med. 2017 Jun;39(6):1477-1491. doi: 10.3892/ijmm.2017.2972. Epub 2017 May 3.
• [5] 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.
• [6] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [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] 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.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.