Details of Drug Off-Target (DOT)

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

• DOT Name: Mucolipin-3 (MCOLN3)
• Synonyms: Transient receptor potential channel mucolipin 3; TRPML3
• Gene Name: MCOLN3
• UniProt ID: MCLN3_HUMAN
• PDB ID: 6AYE; 6AYF; 6AYG
• Pfam ID: PF21381 ; PF08016
• Sequence:
  MADPEVVVSSCSSHEEENRCNFNQQTSPSEELLLEDQMRRKLKFFFMNPCEKFWARGRKP
  WKLAIQILKIAMVTIQLVLFGLSNQMVVAFKEENTIAFKHLFLKGYMDRMDDTYAVYTQS
  DVYDQLIFAVNQYLQLYNVSVGNHAYENKGTKQSAMAICQHFYKRGNIYPGNDTFDIDPE
  IETECFFVEPDEPFHIGTPAENKLNLTLDFHRLLTVELQFKLKAINLQTVRHQELPDCYD
  FTLTITFDNKAHSGRIKISLDNDISIRECKDWHVSGSIQKNTHYMMIFDAFVILTCLVSL
  ILCIRSVIRGLQLQQEFVNFFLLHYKKEVSVSDQMEFVNGWYIMIIISDILTIIGSILKM
  EIQAKSLTSYDVCSILLGTSTMLVWLGVIRYLGFFAKYNLLILTLQAALPNVIRFCCCAA
  MIYLGYCFCGWIVLGPYHDKFRSLNMVSECLFSLINGDDMFATFAKMQQKSYLVWLFSRI
  YLYSFISLFIYMILSLFIALITDTYETIKQYQQDGFPETELRTFISECKDLPNSGKYRLE
  DDPPVSLFCCCKK
• Function: Nonselective ligand-gated cation channel probably playing a role in the regulation of membrane trafficking events. Acts as a Ca(2+)-permeable cation channel with inwardly rectifying activity. Mediates release of Ca(2+) from endosomes to the cytoplasm, contributes to endosomal acidification and is involved in the regulation of membrane trafficking and fusion in the endosomal pathway. Does not seem to act as mechanosensory transduction channel in inner ear sensory hair cells. Proposed to play a critical role at the cochlear stereocilia ankle-link region during hair-bundle growth. Involved in the regulation of autophagy. Through association with GABARAPL2 may be involved in autophagosome formation possibly providing Ca(2+) for the fusion process. Through a possible and probably tissue-specific heteromerization with MCOLN1 may be at least in part involved in many lysosome-dependent cellular events. Possible heteromeric ion channel assemblies with TRPV5 show pharmacological similarity with TRPML3.
• KEGG Pathway: Calcium sig.ling pathway (hsa04020)
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

15 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 Mucolipin-3 (MCOLN3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mucolipin-3 (MCOLN3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mucolipin-3 (MCOLN3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mucolipin-3 (MCOLN3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mucolipin-3 (MCOLN3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mucolipin-3 (MCOLN3).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Mucolipin-3 (MCOLN3).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Mucolipin-3 (MCOLN3).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Mucolipin-3 (MCOLN3).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Mucolipin-3 (MCOLN3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mucolipin-3 (MCOLN3).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Mucolipin-3 (MCOLN3).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mucolipin-3 (MCOLN3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mucolipin-3 (MCOLN3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mucolipin-3 (MCOLN3).	[14]

1 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 increases the methylation of Mucolipin-3 (MCOLN3).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.