Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6DUIYC)

• DOT Name: Endosomal/lysosomal proton channel TMEM175 (TMEM175)
• Synonyms: Potassium channel TMEM175; Transmembrane protein 175; hTMEM175
• Gene Name: TMEM175
• Related Disease:
  Alzheimer disease
  Spondylocarpotarsal synostosis syndrome
  Parkinson disease
• UniProt ID: TM175_HUMAN
• PDB ID: 6W8N; 6W8O; 6W8P; 6WC9; 6WCA; 6WCB; 6WCC; 7LF6; 7UNL; 7UNM; 8DHM; 8FY5; 8FYF
• Pfam ID: PF06736
• Sequence:
  MSQPRTPEQALDTPGDCPPGRRDEDAGEGIQCSQRMLSFSDALLSIIATVMILPVTHTEI
  SPEQQFDRSVQRLLATRIAVYLMTFLIVTVAWAAHTRLFQVVGKTDDTLALLNLACMMTI
  TFLPYTFSLMVTFPDVPLGIFLFCVCVIAIGVVQALIVGYAFHFPHLLSPQIQRSAHRAL
  YRRHVLGIVLQGPALCFAAAIFSLFFVPLSYLLMVTVILLPYVSKVTGWCRDRLLGHREP
  SAHPVEVFSFDLHEPLSKERVEAFSDGVYAIVATLLILDICEDNVPDPKDVKERFSGSLV
  AALSATGPRFLAYFGSFATVGLLWFAHHSLFLHVRKATRAMGLLNTLSLAFVGGLPLAYQ
  QTSAFARQPRDELERVRVSCTIIFLASIFQLAMWTTALLHQAETLQPSVWFGGREHVLMF
  AKLALYPCASLLAFASTCLLSRFSVGIFHLMQIAVPCAFLLLRLLVGLALATLRVLRGLA
  RPEHPPPAPTGQDDPQSQLLPAPC
• Function: Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH. Activated at low pH (under pH 4.6) by luminal side protons: selectively mediates lysosomal proton release from lysosomes, eliciting a proton leak that balances V-ATPase activity to maintain pH homeostasis. Regulation of lumenal pH stability is required for autophagosome-lysosome fusion. Also acts as a potassium channel at higher pH, regulating potassium conductance in endosomes and lysosomes. Constitutes the pore-forming subunit of the lysoK(GF) complex, a complex activated by extracellular growth factors. The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3), a major target of growth factor receptors: in the complex, TMEM175 channel is opened by conformational changes by AKT, leading to its activation. The lysoK(GF) complex is required to protect neurons against stress-induced damage.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Spondylocarpotarsal synostosis syndrome	DISF9VP3	Strong	Altered Expression	[2]
Parkinson disease	DISQVHKL	moderate	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[5]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[8]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[10]

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 affects the methylation of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Endosomal/lysosomal proton channel TMEM175 (TMEM175).	[11]

References

• [1] Association of Parkinson's Disease GWAS-Linked Loci with Alzheimer's Disease in Han Chinese.Mol Neurobiol. 2017 Jan;54(1):308-318. doi: 10.1007/s12035-015-9649-5. Epub 2016 Jan 6.
• [2] Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations.PLoS One. 2018 Jan 2;13(1):e0189498. doi: 10.1371/journal.pone.0189498. eCollection 2018.
• [3] Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.Ann Neurol. 2020 Jan;87(1):139-153. doi: 10.1002/ana.25629. Epub 2019 Nov 18.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [10] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.