Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0J97C6)

• DOT Name: BAG family molecular chaperone regulator 5 (BAG5)
• Synonyms: BAG-5; Bcl-2-associated athanogene 5
• Gene Name: BAG5
• Related Disease:
  Alzheimer disease
  Cardiomyopathy, dilated, 2F
  Epithelial ovarian cancer
  Non-hodgkin lymphoma
  Pancreatic cancer
  Parkinson disease
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Young-onset Parkinson disease
• UniProt ID: BAG5_HUMAN
• PDB ID: 2D9D; 3A8Y
• Pfam ID: PF02179
• Sequence:
  MDMGNQHPSISRLQEIQKEVKSVEQQVIGFSGLSDDKNYKKLERILTKQLFEIDSVDTEG
  KGDIQQARKRAAQETERLLKELEQNANHPHRIEIQNIFEEAQSLVREKIVPFYNGGNCVT
  DEFEEGIQDIILRLTHVKTGGKISLRKARYHTLTKICAVQEIIEDCMKKQPSLPLSEDAH
  PSVAKINFVMCEVNKARGVLIALLMGVNNNETCRHLSCVLSGLIADLDALDVCGRTEIRN
  YRREVVEDINKLLKYLDLEEEADTTKAFDLRQNHSILKIEKVLKRMREIKNELLQAQNPS
  ELYLSSKTELQGLIGQLDEVSLEKNPCIREARRRAVIEVQTLITYIDLKEALEKRKLFAC
  EEHPSHKAVWNVLGNLSEIQGEVLSFDGNRTDKNYIRLEELLTKQLLALDAVDPQGEEKC
  KAARKQAVRLAQNILSYLDLKSDEWEY
• Function: Co-chaperone for HSP/HSP70 proteins. It functions as a nucleotide-exchange factor promoting the release of ADP from HSP70, thereby activating HSP70-mediated protein refolding. Has an essential role in maintaining proteostasis at junctional membrane complexes (JMC), where it may function as a scaffold between the HSPA8 chaperone and JMC proteins enabling correct, HSPA8-dependent JMC protein folding. Inhibits both auto-ubiquitination of PRKN and ubiquitination of target proteins by PRKN.
• Tissue Specificity: Expressed in the heart.
• Reactome Pathway: Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Cardiomyopathy, dilated, 2F	DIS6YW38	Strong	Autosomal recessive	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[3]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[4]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[5]
Parkinson disease	DISQVHKL	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]
Prostate cancer	DISF190Y	Limited	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[7]
Young-onset Parkinson disease	DIS05LFS	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of BAG family molecular chaperone regulator 5 (BAG5).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of BAG family molecular chaperone regulator 5 (BAG5).	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[11]
Menthol	DMG2KW7	Approved	Menthol increases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[12]
Beta-carotene	DM0RXBT	Approved	Beta-carotene decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[15]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[19]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of BAG family molecular chaperone regulator 5 (BAG5).	[20]

References

• [1] Bag5 protects neuronal cells from amyloid -induced cell death.J Mol Neurosci. 2015 Apr;55(4):815-20. doi: 10.1007/s12031-014-0433-1. Epub 2014 Nov 1.
• [2] Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation. Sci Transl Med. 2022 Jan 19;14(628):eabf3274. doi: 10.1126/scitranslmed.abf3274. Epub 2022 Jan 19.
• [3] MicroRNA-127-3p acts as a tumor suppressor in epithelial ovarian cancer by regulating the BAG5 gene.Oncol Rep. 2016 Nov;36(5):2563-2570. doi: 10.3892/or.2016.5055. Epub 2016 Aug 29.
• [4] Germline variation in apoptosis pathway genes and risk of non-Hodgkin's lymphoma.Cancer Epidemiol Biomarkers Prev. 2010 Nov;19(11):2847-58. doi: 10.1158/1055-9965.EPI-10-0581. Epub 2010 Sep 20.
• [5] MicroRNA-127 is aberrantly downregulated and acted as a functional tumor suppressor in human pancreatic cancer.Tumour Biol. 2016 Oct;37(10):14249-14257. doi: 10.1007/s13277-016-5270-0. Epub 2016 Aug 29.
• [6] BAG5 Interacts with DJ-1 and Inhibits the Neuroprotective Effects of DJ-1 to Combat Mitochondrial Oxidative Damage.Oxid Med Cell Longev. 2017;2017:5094934. doi: 10.1155/2017/5094934. Epub 2017 Mar 2.
• [7] Bcl-2 associated athanogene 5 (Bag5) is overexpressed in prostate cancer and inhibits ER-stress induced apoptosis.BMC Cancer. 2013 Mar 1;13:96. doi: 10.1186/1471-2407-13-96.
• [8] BAG5 inhibits parkin and enhances dopaminergic neuron degeneration.Neuron. 2004 Dec 16;44(6):931-45. doi: 10.1016/j.neuron.2004.11.026.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [12] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [13] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [14] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.