Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCT1Y1L)

• DOT Name: Transmembrane protein 163 (TMEM163)
• Gene Name: TMEM163
• Related Disease:
  Alzheimer disease
  Leukodystrophy, hypomyelinating, 25
  Non-insulin dependent diabetes
  Parkinson disease
  Coronary heart disease
  Mucolipidosis type IV
• UniProt ID: TM163_HUMAN
• Sequence:
  MEPAAGIQRRSSQGPTVPPPPRGHAPPAAAPGPAPLSSPVREPPQLEEERQVRISESGQF
  SDGLEDRGLLESSTRLKPHEAQNYRKKALWVSWFSIIVTLALAVAAFTVSVMRYSASAFG
  FAFDAILDVLSSAIVLWRYSNAAAVHSAHREYIACVILGVIFLLSSICIVVKAIHDLSTR
  LLPEVDDFLFSVSILSGILCSILAVLKFMLGKVLTSRALITDGFNSLVGGVMGFSILLSA
  EVFKHDSAVWYLDGSIGVLIGLTIFAYGVKLLIDMVPRVRQTRHYEMFE
• Function: Zinc ion transporter that mediates zinc efflux and plays a crucial role in intracellular zinc homeostasis. Binds the divalent cations Zn(2+), Ni(2+), and to a minor extent Cu(2+). Is a functional modulator of P2X purinoceptors, including P2RX1, P2RX3, P2RX4 and P2RX7. Plays a role in central nervous system development and is required for myelination, and survival and proliferation of oligodendrocytes.
• Tissue Specificity: Widely expressed. High expression is detected in brain, lung and testis.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Leukodystrophy, hypomyelinating, 25	DISBT2X6	Strong	Autosomal dominant	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[3]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[5]
Mucolipidosis type IV	DISWJY3U	moderate	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transmembrane protein 163 (TMEM163).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane protein 163 (TMEM163).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transmembrane protein 163 (TMEM163).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transmembrane protein 163 (TMEM163).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transmembrane protein 163 (TMEM163).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Transmembrane protein 163 (TMEM163).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Transmembrane protein 163 (TMEM163).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transmembrane protein 163 (TMEM163).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Transmembrane protein 163 (TMEM163).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transmembrane protein 163 (TMEM163).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transmembrane protein 163 (TMEM163).	[13]

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] Functional Study of TMEM163 Gene Variants Associated with Hypomyelination Leukodystrophy. Cells. 2022 Apr 9;11(8):1285. doi: 10.3390/cells11081285.
• [3] Role of Tmem163 in zinc-regulated insulin storage of MIN6 cells: Functional exploration of an Indian type 2 diabetes GWAS associated gene.Biochem Biophys Res Commun. 2020 Feb 19;522(4):1022-1029. doi: 10.1016/j.bbrc.2019.11.117. Epub 2019 Dec 6.
• [4] A replication study of GWAS-genetic risk variants associated with Parkinson's disease in a Spanish population.Neurosci Lett. 2019 Nov 1;712:134425. doi: 10.1016/j.neulet.2019.134425. Epub 2019 Aug 17.
• [5] Genomewide association analysis of coronary artery disease.N Engl J Med. 2007 Aug 2;357(5):443-53. doi: 10.1056/NEJMoa072366. Epub 2007 Jul 18.
• [6] Cellular zinc levels are modulated by TRPML1-TMEM163 interaction.Traffic. 2014 Nov;15(11):1247-65. doi: 10.1111/tra.12205. Epub 2014 Sep 2.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] 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.
• [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 signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] 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.