Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHHW2B4)

• DOT Name: Protein disulfide-isomerase TMX3 (TMX3)
• Synonyms: EC 5.3.4.1; Thioredoxin domain-containing protein 10; Thioredoxin-related transmembrane protein 3
• Gene Name: TMX3
• Related Disease:
  Coloboma
  Microphthalmia
• UniProt ID: TMX3_HUMAN
• EC Number: 5.3.4.1
• Pfam ID: PF00085 ; PF13848
• Sequence:
  MAAWKSWTALRLCATVVVLDMVVCKGFVEDLDESFKENRNDDIWLVDFYAPWCGHCKKLE
  PIWNEVGLEMKSIGSPVKVGKMDATSYSSIASEFGVRGYPTIKLLKGDLAYNYRGPRTKD
  DIIEFAHRVSGALIRPLPSQQMFEHMQKRHRVFFVYVGGESPLKEKYIDAASELIVYTYF
  FSASEEVVPEYVTLKEMPAVLVFKDETYFVYDEYEDGDLSSWINRERFQNYLAMDGFLLY
  ELGDTGKLVALAVIDEKNTSVEHTRLKSIIQEVARDYRDLFHRDFQFGHMDGNDYINTLL
  MDELTVPTVVVLNTSNQQYFLLDRQIKNVEDMVQFINNILDGTVEAQGGDSILQRLKRIV
  FDAKSTIVSIFKSSPLMGCFLFGLPLGVISIMCYGIYTADTDGGYIEERYEVSKSENENQ
  EQIEESKEQQEPSSGGSVVPTVQEPKDVLEKKKD
• Function: Probable disulfide isomerase, which participates in the folding of proteins containing disulfide bonds. May act as a dithiol oxidase. Acts as a regulator of endoplasmic reticulum-mitochondria contact sites via its ability to regulate redox signals.
• Tissue Specificity: Widely expressed. Expressed in brain, testis, lung, skin, kidney, uterus, bone, stomach, liver, prostate, placenta, eye and muscle.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coloboma	DISP39N5	Limited	Genetic Variation	[1]
Microphthalmia	DISGEBES	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein disulfide-isomerase TMX3 (TMX3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein disulfide-isomerase TMX3 (TMX3).	[10]

11 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 Protein disulfide-isomerase TMX3 (TMX3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[9]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein disulfide-isomerase TMX3 (TMX3).	[14]

References

• [1] A male with unilateral microphthalmia reveals a role for TMX3 in eye development.PLoS One. 2010 May 11;5(5):e10565. doi: 10.1371/journal.pone.0010565.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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] Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. Anticancer Res. 2015 Nov;35(11):5827-37.
• [9] 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.
• [10] 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.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.