Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTURGRA8)

• DOT Name: Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2)
• Synonyms: MsrB2; EC 1.8.4.12; EC 1.8.4.14
• Gene Name: MSRB2
• UniProt ID: MSRB2_HUMAN
• EC Number: 1.8.4.12; 1.8.4.14
• Pfam ID: PF01641
• Sequence:
  MARLLWLLRGLTLGTAPRRAVRGQAGGGGPGTGPGLGEAGSLATCELPLAKSEWQKKLTP
  EQFYVTREKGTEPPFSGIYLNNKEAGMYHCVCCDSPLFSSEKKYCSGTGWPSFSEAHGTS
  GSDESHTGILRRLDTSLGSARTEVVCKQCEAHLGHVFPDGPGPNGQRFCINSVALKFKPR
  KH
• Function: Methionine-sulfoxide reductase that specifically reduces methionine (R)-sulfoxide back to methionine. While in many cases, methionine oxidation is the result of random oxidation following oxidative stress, methionine oxidation is also a post-translational modification that takes place on specific residue. Upon oxidative stress, may play a role in the preservation of mitochondrial integrity by decreasing the intracellular reactive oxygen species build-up through its scavenging role, hence contributing to cell survival and protein maintenance.
• Tissue Specificity: Ubiquitous. Detected in retina, ocular ciliary body, skeletal muscle, heart, colon, bone marrow, cerebellum, small intestine, fetal brain, fetal liver, kidney, spinal cord, lung, placenta and prostate.
• Reactome Pathway: Protein repair (R-HSA-5676934)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[12]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[16]

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 decreases the methylation of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[17]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the reduction of Methionine-R-sulfoxide reductase B2, mitochondrial (MSRB2).	[18]

References

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• [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] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [12] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [13] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] 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.
• [18] 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.