Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT4C4DI)

• DOT Name: Two pore channel protein 1 (TPCN1)
• Synonyms: Two pore calcium channel protein 1; Voltage-dependent calcium channel protein TPC1
• Gene Name: TPCN1
• UniProt ID: TPC1_HUMAN
• Pfam ID: PF00520
• Sequence:
  MAVSLDDDVPLILTLDEGGSAPLAPSNGLGQEELPSKNGGSYAIHDSQAPSLSSGGESSP
  SSPAHNWEMNYQEAAIYLQEGENNDKFFTHPKDAKALAAYLFAHNHLFYLMELATALLLL
  LLSLCEAPAVPALRLGIYVHATLELFALMVVVFELCMKLRWLGLHTFIRHKRTMVKTSVL
  VVQFVEAIVVLVRQMSHVRVTRALRCIFLVDCRYCGGVRRNLRQIFQSLPPFMDILLLLL
  FFMIIFAILGFYLFSPNPSDPYFSTLENSIVSLFVLLTTANFPDVMMPSYSRNPWSCVFF
  IVYLSIELYFIMNLLLAVVFDTFNDIEKRKFKSLLLHKRTAIQHAYRLLISQRRPAGISY
  RQFEGLMRFYKPRMSARERYLTFKALNQNNTPLLSLKDFYDIYEVAALKWKAKKNREHWF
  DELPRTALLIFKGINILVKSKAFQYFMYLVVAVNGVWILVETFMLKGGNFFSKHVPWSYL
  VFLTIYGVELFLKVAGLGPVEYLSSGWNLFDFSVTVFAFLGLLALALNMEPFYFIVVLRP
  LQLLRLFKLKERYRNVLDTMFELLPRMASLGLTLLIFYYSFAIVGMEFFCGIVFPNCCNT
  STVADAYRWRNHTVGNRTVVEEGYYYLNNFDNILNSFVTLFELTVVNNWYIIMEGVTSQT
  SHWSRLYFMTFYIVTMVVMTIIVAFILEAFVFRMNYSRKNQDSEVDGGITLEKEISKEEL
  VAVLELYREARGASSDVTRLLETLSQMERYQQHSMVFLGRRSRTKSDLSLKMYQEEIQEW
  YEEHAREQEQQRQLSSSAAPAAQQPPGSRQRSQTVT
• Function: Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a voltage-gated highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and confers electrical excitability to organelles. Localizes to the early and recycling endosomes membranes where it plays a role in the uptake and processing of proteins and regulates organellar membrane excitability, membrane trafficking and pH homeostasis (Probable). Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions, can be readily activated by both NAADP and PI(3,5)P2 (Probable). Required for mTOR-dependent nutrient sensing (Probable); (Microbial infection) During Ebola virus (EBOV) infection, controls the movement of endosomes containing virus particles and is required by EBOV to escape from the endosomal network into the cell cytoplasm.
• Tissue Specificity: Highest expression found in the heart and kidney, and lowest expression found in the spleen.
• KEGG Pathway: Calcium sig.ling pathway (hsa04020)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Two pore channel protein 1 (TPCN1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Two pore channel protein 1 (TPCN1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Two pore channel protein 1 (TPCN1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Two pore channel protein 1 (TPCN1).	[1]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Two pore channel protein 1 (TPCN1).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Two pore channel protein 1 (TPCN1).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Two pore channel protein 1 (TPCN1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Two pore channel protein 1 (TPCN1).	[1]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Two pore channel protein 1 (TPCN1).	[1]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Two pore channel protein 1 (TPCN1).	[1]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Two pore channel protein 1 (TPCN1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Two pore channel protein 1 (TPCN1).	[9]
MGCD-0103	DM726HX	Phase 2	MGCD-0103 increases the expression of Two pore channel protein 1 (TPCN1).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Two pore channel protein 1 (TPCN1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Two pore channel protein 1 (TPCN1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Two pore channel protein 1 (TPCN1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Two pore channel protein 1 (TPCN1).	[14]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Two pore channel protein 1 (TPCN1).	[15]
Manganese	DMKT129	Investigative	Manganese increases the expression of Two pore channel protein 1 (TPCN1).	[16]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of Two pore channel protein 1 (TPCN1).	[6]
DZNep	DM0JXBK	Investigative	DZNep decreases the expression of Two pore channel protein 1 (TPCN1).	[6]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Two pore channel protein 1 (TPCN1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Two pore channel protein 1 (TPCN1).	[10]

References

• [1] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] 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.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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 profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [16] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.