Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8FX82D)

• DOT Name: Transmembrane channel-like protein 4 (TMC4)
• Gene Name: TMC4
• Related Disease:
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Liver cirrhosis
  Non-alcoholic fatty liver disease
• UniProt ID: TMC4_HUMAN
• Pfam ID: PF07810
• Sequence:
  MEENPTLESEAWGSSRGWLAPREARGAPCSSPGPSLSSVLNELPSAATLRYRDPGVLPWG
  ALEEEEEDGGRSRKAFTEVTQTELQDPHPSRELPWPMQARRAHRQRNASRDQVVYGSGTK
  TDRWARLLRRSKEKTKEGLRSLQPWAWTLKRIGGQFGAGTESYFSLLRFLLLLNVLASVL
  MACMTLLPTWLGGAPPGPPGPDISSPCGSYNPHSQGLVTFATQLFNLLSGEGYLEWSPLF
  YGFYPPRPRLAVTYLCWAFAVGLICLLLILHRSVSGLKQTLLAESEALTSYSHRVFSAWD
  FGLCGDVHVRLRQRIILYELKVELEETVVRRQAAVRTLGQQARVWLVRVLLNLLVVALLG
  AAFYGVYWATGCTVELQEMPLVQELPLLKLGVNYLPSIFIAGVNFVLPPVFKLIAPLEGY
  TRSRQIVFILLRTVFLRLASLVVLLFSLWNQITCGGDSEAEDCKTCGYNYKQLPCWETVL
  GQEMYKLLLFDLLTVLAVALLIQFPRKLLCGLCPGALGRLAGTQEFQVPDEVLGLIYAQT
  VVWVGSFFCPLLPLLNTVKFLLLFYLKKLTLFSTCSPAARTFRASAANFFFPLVLLLGLA
  ISSVPLLYSIFLIPPSKLCGPFRGQSSIWAQIPESISSLPETTQNFLFFLGTQAFAVPLL
  LISSILMAYTVALANSYGRLISELKRQRQTEAQNKVFLARRAVALTSTKPAL
• Function: Probable ion channel.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyloidosis	DISHTAI2	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[3]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[4]

2 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 Transmembrane channel-like protein 4 (TMC4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane channel-like protein 4 (TMC4).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane channel-like protein 4 (TMC4).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transmembrane channel-like protein 4 (TMC4).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transmembrane channel-like protein 4 (TMC4).	[7]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Transmembrane channel-like protein 4 (TMC4).	[9]

References

• [1] Genetic resilience to amyloid related cognitive decline.Brain Imaging Behav. 2017 Apr;11(2):401-409. doi: 10.1007/s11682-016-9615-5.
• [2] Tumor expression of environmental chemical-responsive genes and breast cancer mortality.Endocr Relat Cancer. 2019 Dec;26(12):843-851. doi: 10.1530/ERC-19-0357.
• [3] The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.Gastroenterology. 2016 May;150(5):1219-1230.e6. doi: 10.1053/j.gastro.2016.01.032. Epub 2016 Feb 2.
• [4] Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7- intergenic downstream variant-in the Susceptibility to Nonalcoholic Fatty Liver Disease.Sci Rep. 2018 Mar 23;8(1):5097. doi: 10.1038/s41598-018-23453-9.
• [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] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] 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.
• [9] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.