Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4UZXMN)

• DOT Name: Methionine-R-sulfoxide reductase B3 (MSRB3)
• Synonyms: MsrB3; EC 1.8.4.12; EC 1.8.4.14
• Gene Name: MSRB3
• Related Disease:
  Nonsyndromic genetic hearing loss
  Advanced cancer
  Alzheimer disease
  Autosomal recessive nonsyndromic hearing loss 74
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Deafness
  Stroke
  Hearing loss, autosomal recessive
  Neoplasm
• UniProt ID: MSRB3_HUMAN
• PDB ID: 6QA0
• EC Number: 1.8.4.12; 1.8.4.14
• Pfam ID: PF01641
• Sequence:
  MSPRRTLPRPLSLCLSLCLCLCLAAALGSAQSGSCRDKKNCKVVFSQQELRKRLTPLQYH
  VTQEKGTESAFEGEYTHHKDPGIYKCVVCGTPLFKSETKFDSGSGWPSFHDVINSEAITF
  TDDFSYGMHRVETSCSQCGAHLGHIFDDGPRPTGKRYCINSAALSFTPADSSGTAEGGSG
  VASPAQADKAEL
• Function: Catalyzes the reduction of free and protein-bound methionine sulfoxide to methionine. Isoform 2 is essential for hearing.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Protein repair (R-HSA-5676934)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Autosomal recessive nonsyndromic hearing loss 74	DIS4UT0F	Strong	Autosomal recessive	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Cervical cancer	DISFSHPF	Strong	Biomarker	[6]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[6]
Deafness	DISKCLH4	Strong	Biomarker	[7]
Stroke	DISX6UHX	Strong	Genetic Variation	[3]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[9]

12 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 Methionine-R-sulfoxide reductase B3 (MSRB3).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[20]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Methionine-R-sulfoxide reductase B3 (MSRB3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Methionine-R-sulfoxide reductase B3 (MSRB3).	[19]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the reduction of Methionine-R-sulfoxide reductase B3 (MSRB3).	[22]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] MsrB3 deficiency induces cancer cell apoptosis through p53-independent and ER stress-dependent pathways.Arch Biochem Biophys. 2017 May 1;621:1-5. doi: 10.1016/j.abb.2017.04.001. Epub 2017 Apr 5.
• [3] Methionine Sulfoxide Reductase-B3 Risk Allele Implicated in Alzheimer's Disease Associates with Increased Odds for Brain Infarcts.J Alzheimers Dis. 2019;68(1):357-365. doi: 10.3233/JAD-180977.
• [4] Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am J Hum Genet. 2011 Jan 7;88(1):19-29. doi: 10.1016/j.ajhg.2010.11.010. Epub 2010 Dec 23.
• [5] A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability.Nat Med. 2017 May;23(5):568-578. doi: 10.1038/nm.4323. Epub 2017 Apr 10.
• [6] A three-gene novel predictor for improving the prognosis of cervical cancer.Oncol Lett. 2019 Nov;18(5):4907-4915. doi: 10.3892/ol.2019.10815. Epub 2019 Sep 5.
• [7] Methionine sulfoxide reductase B3 deficiency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells.Hum Mol Genet. 2014 Mar 15;23(6):1591-601. doi: 10.1093/hmg/ddt549. Epub 2013 Nov 3.
• [8] [Gene therapy for human hearing loss: challenges and promises]. Med Sci (Paris). 2013 Oct;29(10):883-9. doi: 10.1051/medsci/20132910016. Epub 2013 Oct 18.
• [9] Increased expression of methionine sulfoxide reductases B3 is associated with poor prognosis in gastric cancer.Oncol Lett. 2019 Jul;18(1):465-471. doi: 10.3892/ol.2019.10318. Epub 2019 May 6.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [22] Thionein can serve as a reducing agent for the methionine sulfoxide reductases. Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8656-61. doi: 10.1073/pnas.0602826103. Epub 2006 May 30.