Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX4FHYQ)

• DOT Name: Thioredoxin-related transmembrane protein 1 (TMX1)
• Synonyms: Protein disulfide-isomerase TMX1; EC 5.3.4.1; Thioredoxin domain-containing protein 1; Transmembrane Trx-related protein
• Gene Name: TMX1
• Related Disease:
  Advanced cancer
  Bladder cancer
  Epilepsy
  Herpes simplex infection
  Skin disease
  Transitional cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Urothelial carcinoma
  Diabetic neuropathy
  Breast cancer
  Breast carcinoma
• UniProt ID: TMX1_HUMAN
• PDB ID: 1X5E
• EC Number: 5.3.4.1
• Pfam ID: PF00085
• Sequence:
  MAPSGSLAVPLAVLVLLLWGAPWTHGRRSNVRVITDENWRELLEGDWMIEFYAPWCPACQ
  NLQPEWESFAEWGEDLEVNIAKVDVTEQPGLSGRFIITALPTIYHCKDGEFRRYQGPRTK
  KDFINFISDKEWKSIEPVSSWFGPGSVLMSSMSALFQLSMWIRTCHNYFIEDLGLPVWGS
  YTVFALATLFSGLLLGLCMIFVADCLCPSKRRRPQPYPYPSKKLLSESAQPLKKVEEEQE
  ADEEDVSEEEAESKEGTNKDFPQNAIRQRSLGPSLATDKS
• Function: Thiredoxin domain-containing protein that participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyze dithiol-disulfide exchange reactions. Acts as a key inhibitor of the alternative triglyceride biosynthesis pathway by inhibiting the activity of TMEM68/DIESL at the endoplasmic reticulum, thereby restricting accumulation of triacylglycerol. The alternative triglyceride biosynthesis pathway mediates formation of triacylglycerol from diacylglycerol and membrane phospholipids. Acts as a protein disulfide isomerase by catalyzing formation or reduction of disulfide bonds. Specifically mediates formation of disulfide bonds of transmembrane proteins at the endoplasmic reticulum membrane. Involved in endoplasmic reticulum-associated degradation (ERAD) via its protein disulfide isomerase activity by acting on folding-defective polypeptides at the endoplasmic reticulum membrane. Acts as a negative regulator of platelet aggregation following secretion in the extracellular space. Acts as a regulator of endoplasmic reticulum-mitochondria contact sites via its ability to regulate redox signals. Regulates endoplasmic reticulum-mitochondria Ca(2+) flux.
• Tissue Specificity: Ubiquitous . Highly expressed in kidney, liver, placenta and lung .

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[4]
Skin disease	DISDW8R6	Strong	Biomarker	[5]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[2]
Diabetic neuropathy	DISX6VF8	moderate	Biomarker	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[7]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[12]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[20]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Thioredoxin-related transmembrane protein 1 (TMX1).	[21]

2 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 increases the methylation of Thioredoxin-related transmembrane protein 1 (TMX1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Thioredoxin-related transmembrane protein 1 (TMX1).	[17]

References

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• [2] A placebo-controlled efficacy study of the intravesical immunomodulators TMX-101 and TMX-202 in an orthotopic bladder cancer rat model.World J Urol. 2018 Nov;36(11):1719-1725. doi: 10.1007/s00345-018-2334-3. Epub 2018 May 16.
• [3] Oestrogen receptor ER and ER agonists ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure.Exp Physiol. 2019 Dec;104(12):1911-1928. doi: 10.1113/EP087986. Epub 2019 Nov 15.
• [4] Establishment and characterization of an immortalized renal cell line of the Chinese tree shrew (Tupaia belangeri chinesis).Appl Microbiol Biotechnol. 2019 Mar;103(5):2171-2180. doi: 10.1007/s00253-019-09615-3. Epub 2019 Jan 12.
• [5] Inhibition of keratinocyte proliferation by phospholipid-conjugates of a TLR7 ligand in a Myc-induced hyperplastic actinic keratosis model in the absence of systemic side effects.Eur J Dermatol. 2013 Sep-Oct;23(5):618-28. doi: 10.1684/ejd.2013.2155.
• [6] Characterization of Nave and Vitamin C-Treated Mouse Schwann Cell Line MSC80: Induction of the Antioxidative Thioredoxin Related Transmembrane Protein 1.J Proteome Res. 2018 Sep 7;17(9):2925-2936. doi: 10.1021/acs.jproteome.8b00022. Epub 2018 Aug 10.
• [7] Estrogen receptor alpha (ERS1) SNPs c454-397T>C (PvuII) and c454-351A>G (XbaI) are risk biomarkers for breast cancer development.Mol Biol Rep. 2014 Aug;41(8):5459-66. doi: 10.1007/s11033-014-3419-8. Epub 2014 Jun 14.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] 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.
• [11] 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.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] 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.
• [14] 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.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [21] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.