Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM9O21K)

• DOT Name: Thioredoxin-related transmembrane protein 2 (TMX2)
• Synonyms: Cell proliferation-inducing gene 26 protein; Thioredoxin domain-containing protein 14
• Gene Name: TMX2
• Related Disease:
  Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity
  Schizophrenia
  Breast cancer
  Breast carcinoma
• UniProt ID: TMX2_HUMAN
• PDB ID: 2DJ0
• Pfam ID: PF00085
• Sequence:
  MAVLAPLIALVYSVPRLSRWLAQPYYLLSALLSAAFLLVRKLPPLCHGLPTQREDGNPCD
  FDWREVEILMFLSAIVMMKNRRSITVEQHIGNIFMFSKVANTILFFRLDIRMGLLYITLC
  IVFLMTCKPPLYMGPEYIKYFNDKTIDEELERDKRVTWIVEFFANWSNDCQSFAPIYADL
  SLKYNCTGLNFGKVDVGRYTDVSTRYKVSTSPLTKQLPTLILFQGGKEAMRRPQIDKKGR
  AVSWTFSEENVIREFNLNELYQRAKKLSKAGDNIPEEQPVASTPTTVSDGENKKDK
• Function: Endoplasmic reticulum and mitochondria-associated protein that probably functions as a regulator of cellular redox state and thereby regulates protein post-translational modification, protein folding and mitochondrial activity. Indirectly regulates neuronal proliferation, migration, and organization in the developing brain.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity	DIS153ZV	Strong	Autosomal recessive	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Limited	Biomarker	[3]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[3]

3 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 Thioredoxin-related transmembrane protein 2 (TMX2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Thioredoxin-related transmembrane protein 2 (TMX2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Thioredoxin-related transmembrane protein 2 (TMX2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thioredoxin-related transmembrane protein 2 (TMX2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thioredoxin-related transmembrane protein 2 (TMX2).	[6]

References

• [1] Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly. J Med Genet. 2020 Apr;57(4):274-282. doi: 10.1136/jmedgenet-2019-106409. Epub 2019 Oct 5.
• [2] Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.Nat Genet. 2018 Mar;50(3):381-389. doi: 10.1038/s41588-018-0059-2. Epub 2018 Feb 26.
• [3] SKP2 overexpression is associated with increased serine 10 phosphorylation of p27 (pSer10p27) in triple-negative breast cancer.J Cell Physiol. 2014 Sep;229(9):1160-9. doi: 10.1002/jcp.24545.
• [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] 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.
• [6] 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.
• [7] 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.
• [8] 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.