Details of Drug Off-Target (DOT)

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

• DOT Name: Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB)
• Synonyms: MCUb; Coiled-coil domain-containing protein 109B
• Gene Name: MCUB
• Related Disease:
  Age-related macular degeneration
  Atopic dermatitis
  Glioma
• UniProt ID: MCUB_HUMAN
• Pfam ID: PF04678
• Sequence:
  MLQRGLWPWRTRLLPTPGTWRPARPWPLPPPPQVLRVKLCGNVKYYQSHHYSTVVPPDEI
  TVIYRHGLPLVTLTLPSRKERCQFVVKPMLSTVGSFLQDLQNEDKGIKTAAIFTADGNMI
  SASTLMDILLMNDFKLVINKIAYDVQCPKREKPSNEHTAEMEHMKSLVHRLFTILHLEES
  QKKREHHLLEKIDHLKEQLQPLEQVKAGIEAHSEAKTSGLLWAGLALLSIQGGALAWLTW
  WVYSWDIMEPVTYFITFANSMVFFAYFIVTRQDYTYSAVKSRQFLQFFHKKSKQQHFDVQ
  QYNKLKEDLAKAKESLKQARHSLCLQMQVEELNEKN
• Function: Negatively regulates the activity of MCU, the mitochondrial inner membrane calcium uniporter, and thereby modulates calcium uptake into the mitochondrion. Does not form functional calcium channels by itself. Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways.
• Reactome Pathway:
  Processing of SMDT1 (R-HSA-8949664)
  Mitochondrial calcium ion transport (R-HSA-8949215)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Posttranslational Modification	[3]

17 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 Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Calcium uniporter regulatory subunit MCUb, mitochondrial (MCUB).	[19]

References

• [1] Seven new loci associated with age-related macular degeneration.Nat Genet. 2013 Apr;45(4):433-9, 439e1-2. doi: 10.1038/ng.2578. Epub 2013 Mar 3.
• [2] Mechanisms of IFN--induced apoptosis of human skin keratinocytes in patients with atopic dermatitis.J Allergy Clin Immunol. 2012 May;129(5):1297-306. doi: 10.1016/j.jaci.2012.02.020. Epub 2012 Mar 24.
• [3] Coiled-coil domain containing 109B is a HIF1-regulated gene critical for progression of human gliomas.J Transl Med. 2017 Jul 28;15(1):165. doi: 10.1186/s12967-017-1266-9.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] 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.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.