Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKF1VBT)

• DOT Name: DnaJ homolog subfamily A member 2 (DNAJA2)
• Synonyms: Cell cycle progression restoration gene 3 protein; Dnj3; Dj3; HIRA-interacting protein 4; Renal carcinoma antigen NY-REN-14
• Gene Name: DNAJA2
• Related Disease:
  Fibrolamellar liver cancer
  Huntington disease
  Parkinsonian disorder
  Gastric cancer
  Parkinson disease
  Rheumatoid arthritis
• UniProt ID: DNJA2_HUMAN
• PDB ID: 7ZHS
• Pfam ID: PF00226 ; PF01556 ; PF00684
• Sequence:
  MANVADTKLYDILGVPPGASENELKKAYRKLAKEYHPDKNPNAGDKFKEISFAYEVLSNP
  EKRELYDRYGEQGLREGSGGGGGMDDIFSHIFGGGLFGFMGNQSRSRNGRRRGEDMMHPL
  KVSLEDLYNGKTTKLQLSKNVLCSACSGQGGKSGAVQKCSACRGRGVRIMIRQLAPGMVQ
  QMQSVCSDCNGEGEVINEKDRCKKCEGKKVIKEVKILEVHVDKGMKHGQRITFTGEADQA
  PGVEPGDIVLLLQEKEHEVFQRDGNDLHMTYKIGLVEALCGFQFTFKHLDGRQIVVKYPP
  GKVIEPGCVRVVRGEGMPQYRNPFEKGDLYIKFDVQFPENNWINPDKLSELEDLLPSRPE
  VPNIIGETEEVELQEFDSTRGSGGGQRREAYNDSSDEESSSHHGPGVQCAHQ
• Function: Co-chaperone of Hsc70. Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B (in vitro).
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fibrolamellar liver cancer	DISUDA2P	Strong	Altered Expression	[1]
Huntington disease	DISQPLA4	Strong	Biomarker	[2]
Parkinsonian disorder	DISHGY45	Disputed	Genetic Variation	[3]
Gastric cancer	DISXGOUK	Limited	Biomarker	[4]
Parkinson disease	DISQVHKL	Limited	Biomarker	[5]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[10]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[9]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of DnaJ homolog subfamily A member 2 (DNAJA2).	[15]

References

• [1] An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma.Elife. 2019 May 7;8:e44187. doi: 10.7554/eLife.44187.
• [2] Suppression of protein aggregation by chaperone modification of high molecular weight complexes.Brain. 2012 Apr;135(Pt 4):1180-96. doi: 10.1093/brain/aws022. Epub 2012 Mar 6.
• [3] DNAJC13 p.Asn855Ser, implicated in familial parkinsonism, alters membrane dynamics of sorting nexin 1.Neurosci Lett. 2019 Jul 27;706:114-122. doi: 10.1016/j.neulet.2019.04.043. Epub 2019 May 11.
• [4] HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer.OMICS. 2017 May;21(5):257-265. doi: 10.1089/omi.2017.0016.
• [5] Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson's disease.Neurogenetics. 2006 Mar;7(1):1-11. doi: 10.1007/s10048-005-0020-2. Epub 2006 Jan 12.
• [6] Isolation of an IgG monoclonal anti-dnaJ antibody from an immunoglobulin combinatorial library from a patient with rheumatoid arthritis.J Rheumatol. 1999 Jul;26(7):1439-45.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [12] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [13] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [15] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.