Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB7BAFQ)

• DOT Name: BRCA1-associated protein (BRAP)
• Synonyms: EC 2.3.2.27; BRAP2; Impedes mitogenic signal propagation; IMP; RING finger protein 52; RING-type E3 ubiquitin transferase BRAP2; Renal carcinoma antigen NY-REN-63
• Gene Name: BRAP
• Related Disease:
  Bacteremia
  Cryptosporidium infection
  Hepatitis B virus infection
  Lewy body dementia
  Advanced cancer
  Alcohol dependence
  Arteriosclerosis
  Atherosclerosis
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Cardiac disease
  Cardiovascular disease
  Cerebral infarction
  Chromosomal disorder
  Chronic kidney disease
  Clear cell renal carcinoma
  Colon cancer
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Glioma
  Glycogen storage disease VII
  Hereditary breast carcinoma
  Intellectual disability
  Kidney cancer
  Neonatal-onset encephalopathy with rigidity and seizures
  Neoplasm
  Neuralgia
  Ovarian cancer
  Pseudomonas infection
  Pulmonary arterial hypertension
  Retinitis pigmentosa
  Schizophrenia
  Stroke
  Uveal Melanoma
  Alcohol-induced disorders
  Alcohol-related disorders
  Coronary heart disease
  Obesity
  Type-1/2 diabetes
  Alzheimer disease
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Non-insulin dependent diabetes
  Sickle-cell anaemia
  Systemic primary carnitine deficiency disease
• UniProt ID: BRAP_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF07576 ; PF13639 ; PF02148
• Sequence:
  MSVSLVVIRLELAEHSPVPAGFGFSAAAGEMSDEEIKKTTLASAVACLEGKSPGEKVAII
  HQHLGRREMTDVIIETMKSNPDELKTTVEERKSSEASPTAQRSKDHSKECINAAPDSPSK
  QLPDQISFFSGNPSVEIVHGIMHLYKTNKMTSLKEDVRRSAMLCILTVPAAMTSHDLMKF
  VAPFNEVIEQMKIIRDSTPNQYMVLIKFRAQADADSFYMTCNGRQFNSIEDDVCQLVYVE
  RAEVLKSEDGASLPVMDLTELPKCTVCLERMDESVNGILTTLCNHSFHSQCLQRWDDTTC
  PVCRYCQTPEPVEENKCFECGVQENLWICLICGHIGCGRYVSRHAYKHFEETQHTYAMQL
  TNHRVWDYAGDNYVHRLVASKTDGKIVQYECEGDTCQEEKIDALQLEYSYLLTSQLESQR
  IYWENKIVRIEKDTAEEINNMKTKFKETIEKCDNLEHKLNDLLKEKQSVERKCTQLNTKV
  AKLTNELKEEQEMNKCLRANQVLLQNKLKEEERVLKETCDQKDLQITEIQEQLRDVMFYL
  ETQQKINHLPAETRQEIQEGQINIAMASASSPASSGGSGKLPSRKGRSKRGK
• Function: Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein. Also acts as a Ras responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination resulting in the release of inhibition of Raf/MEK complex formation. May also act as a cytoplasmic retention protein with a role in regulating nuclear transport.
• Tissue Specificity: Expressed in breast epithelial cell lines.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway:
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  RAF activation (R-HSA-5673000)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Biomarker	[1]
Cryptosporidium infection	DISLBTU2	Definitive	Biomarker	[2]
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[3]
Lewy body dementia	DISAE66J	Definitive	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[6]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[7]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[7]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Cardiac disease	DISVO1I5	Strong	Biomarker	[10]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[9]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[11]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[12]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[13]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[14]
Colon cancer	DISVC52G	Strong	Biomarker	[15]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[16]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[17]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[18]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[18]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Glycogen storage disease VII	DISWZUF2	Strong	Altered Expression	[19]
Hereditary breast carcinoma	DISAEZT5	Strong	Genetic Variation	[18]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[20]
Kidney cancer	DISBIPKM	Strong	Genetic Variation	[14]
Neonatal-onset encephalopathy with rigidity and seizures	DIS8U111	Strong	Genetic Variation	[20]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neuralgia	DISWO58J	Strong	Biomarker	[21]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[22]
Pseudomonas infection	DIS9WYLA	Strong	Biomarker	[23]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Genetic Variation	[24]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[25]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[26]
Stroke	DISX6UHX	Strong	Biomarker	[7]
Uveal Melanoma	DISA7ZGL	Strong	Genetic Variation	[27]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[28]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[28]
Coronary heart disease	DIS5OIP1	moderate	Biomarker	[9]
Obesity	DIS47Y1K	moderate	Genetic Variation	[29]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[30]
Alzheimer disease	DISF8S70	Limited	Biomarker	[4]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Limited	Altered Expression	[31]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[32]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[33]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of BRCA1-associated protein (BRAP).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BRCA1-associated protein (BRAP).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of BRCA1-associated protein (BRAP).	[36]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of BRCA1-associated protein (BRAP).	[37]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of BRCA1-associated protein (BRAP).	[38]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BRCA1-associated protein (BRAP).	[40]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of BRCA1-associated protein (BRAP).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of BRCA1-associated protein (BRAP).	[39]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of BRCA1-associated protein (BRAP).	[39]

References

• [1] Molecular and epidemiological characterization of IMP-type metallo--lactamase-producing Enterobacter cloacae in a Large tertiary care hospital in Japan.Antimicrob Agents Chemother. 2014 Jun;58(6):3441-50. doi: 10.1128/AAC.02652-13. Epub 2014 Apr 7.
• [2] Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis.Antimicrob Agents Chemother. 2014;58(3):1603-14. doi: 10.1128/AAC.02075-13. Epub 2013 Dec 23.
• [3] A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population.Hum Mol Genet. 2011 Oct 1;20(19):3884-92. doi: 10.1093/hmg/ddr301. Epub 2011 Jul 12.
• [4] The Cingulate Island Sign on FDG-PET vs. IMP-SPECT to Assess Mild Cognitive Impairment in Alzheimer's Disease vs. Dementia with Lewy Bodies.J Neuroimaging. 2019 Nov;29(6):712-720. doi: 10.1111/jon.12643. Epub 2019 Jun 14.
• [5] BRCA1-associated protein inhibits glioma cell proliferation and migration and glioma stem cell self-renewal via the TGF-/PI3K/AKT/mTOR signalling pathway.Cell Oncol (Dordr). 2020 Apr;43(2):223-235. doi: 10.1007/s13402-019-00482-8. Epub 2019 Nov 27.
• [6] Associations of BRAP polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test.Neuropsychiatr Dis Treat. 2018 Dec 24;15:83-94. doi: 10.2147/NDT.S184067. eCollection 2019.
• [7] Lack of association between a functional variant of the BRCA-1 related associated protein (BRAP) gene and ischemic stroke.BMC Med Genet. 2013 Jan 28;14:17. doi: 10.1186/1471-2350-14-17.
• [8] A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder.Mol Psychiatry. 1997 Sep;2(5):393-7. doi: 10.1038/sj.mp.4000325.
• [9] The single nucleotide polymorphisms in BRAP decrease the risk of metabolic syndrome in a Chinese young adult population.Diab Vasc Dis Res. 2013 May;10(3):202-7. doi: 10.1177/1479164112455535. Epub 2012 Sep 10.
• [10] Patterns of Multimorbidity in a Population-Based Cohort of Older People: Sociodemographic, Lifestyle, Clinical, and Functional Differences.J Gerontol A Biol Sci Med Sci. 2020 Mar 9;75(4):798-805. doi: 10.1093/gerona/glz137.
• [11] pSY153-MDR, a p12969-DIM-related mega plasmid carrying bla(IMP-45) and armA, from clinical Pseudomonas putida.Oncotarget. 2017 Jul 22;8(40):68439-68447. doi: 10.18632/oncotarget.19496. eCollection 2017 Sep 15.
• [12] ITPA protein, an enzyme that eliminates deaminated purine nucleoside triphosphates in cells.Mutat Res. 2010 Nov 28;703(1):43-50. doi: 10.1016/j.mrgentox.2010.06.009. Epub 2010 Jun 22.
• [13] Association between kidney function and genetic polymorphisms in atherosclerotic and chronic kidney diseases: A cross-sectional study in Japanese male workers.PLoS One. 2017 Oct 10;12(10):e0185476. doi: 10.1371/journal.pone.0185476. eCollection 2017.
• [14] A BAP1 Mutation-specific MicroRNA Signature Predicts Clinical Outcomes in Clear Cell Renal Cell Carcinoma Patients with Wild-type BAP1.J Cancer. 2017 Aug 21;8(13):2643-2652. doi: 10.7150/jca.20234. eCollection 2017.
• [15] Antimicrobial susceptibilities of specific syndromes created with organ-specific weighted incidence antibiograms (OSWIA) in patients with intra-abdominal infections.BMC Infect Dis. 2018 Nov 19;18(1):584. doi: 10.1186/s12879-018-3494-x.
• [16] Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations.Nat Genet. 2011 Jun 5;43(7):679-84. doi: 10.1038/ng.849.
• [17] BRCA1-Associated Protein Increases Invasiveness of Esophageal Squamous Cell Carcinoma.Gastroenterology. 2017 Nov;153(5):1304-1319.e5. doi: 10.1053/j.gastro.2017.07.042. Epub 2017 Aug 2.
• [18] Screening for large genomic rearrangements of the BRIP1 and CHK1 genes in Finnish breast cancer families.Fam Cancer. 2010 Dec;9(4):537-40. doi: 10.1007/s10689-010-9360-7.
• [19] The contribution of Ca+ calmodulin activation of human erythrocyte AMP deaminase (isoform E) to the erythrocyte metabolic dysregulation of familial phosphofructokinase deficiency.Haematologica. 2006 May;91(5):652-5.
• [20] Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1.Ophthalmic Genet. 2017 Dec;38(6):559-561. doi: 10.1080/13816810.2017.1290118. Epub 2017 Mar 2.
• [21] Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain.J Neurol Neurosurg Psychiatry. 2018 Oct;89(10):1082-1087. doi: 10.1136/jnnp-2017-316601. Epub 2018 Apr 7.
• [22] Expression of the RNA-binding protein IMP1 correlates with poor prognosis in ovarian carcinoma.Oncogene. 2007 Nov 29;26(54):7584-9. doi: 10.1038/sj.onc.1210563. Epub 2007 Jun 4.
• [23] Nosocomial infections caused by multidrug-resistant isolates of pseudomonas putida producing VIM-1 metallo-beta-lactamase.J Clin Microbiol. 2002 Nov;40(11):4051-5. doi: 10.1128/JCM.40.11.4051-4055.2002.
• [24] Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension.PLoS One. 2019 Jan 31;14(1):e0211450. doi: 10.1371/journal.pone.0211450. eCollection 2019.
• [25] IMP dehydrogenase-linked retinitis pigmentosa.Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):839-49. doi: 10.1080/15257770802146486.
• [26] A two-stage association study suggests BRAP as a susceptibility gene for schizophrenia.PLoS One. 2014 Jan 15;9(1):e86037. doi: 10.1371/journal.pone.0086037. eCollection 2014.
• [27] PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma.Cancers (Basel). 2019 May 29;11(6):751. doi: 10.3390/cancers11060751.
• [28] Genome-wide association study of alcohol dependence in male Han Chinese and cross-ethnic polygenic risk score comparison.Transl Psychiatry. 2019 Oct 7;9(1):249. doi: 10.1038/s41398-019-0586-3.
• [29] Effect of dietary energy and polymorphisms in BRAP and GHRL on obesity and metabolic traits.Obes Res Clin Pract. 2018 Jan-Feb;12(Suppl 2):39-48. doi: 10.1016/j.orcp.2016.05.004. Epub 2016 May 27.
• [30] Synergistic effect between BRAP polymorphism and diabetes on the extent of coronary atherosclerosis in the Chinese population.Cardiology. 2011;120(1):3-8. doi: 10.1159/000332592. Epub 2011 Nov 11.
• [31] Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis.Anticancer Res. 1996 Nov-Dec;16(6A):3349-51.
• [32] IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes.J Mol Endocrinol. 2009 Nov;43(5):187-95. doi: 10.1677/JME-09-0016. Epub 2009 May 8.
• [33] Arterial spin labeling MR imaging for the clinical detection of cerebellar hypoperfusion in patients with spinocerebellar degeneration.J Neurol Sci. 2018 Nov 15;394:58-62. doi: 10.1016/j.jns.2018.09.007. Epub 2018 Sep 6.
• [34] 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.
• [35] 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.
• [36] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [37] 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.
• [38] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [39] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [40] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [41] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.