Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAC2K95)

• DOT Name: DnaJ homolog subfamily B member 14 (DNAJB14)
• Gene Name: DNAJB14
• UniProt ID: DJB14_HUMAN
• Pfam ID: PF00226 ; PF09320
• Sequence:
  MEGNRDEAEKCVEIAREALNAGNREKAQRFLQKAEKLYPLPSARALLEIIMKNGSTAGNS
  PHCRKPSGSGDQSKPNCTKDSTSGSGEGGKGYTKDQVDGVLSINKCKNYYEVLGVTKDAG
  DEDLKKAYRKLALKFHPDKNHAPGATDAFKKIGNAYAVLSNPEKRKQYDLTGNEEQACNH
  QNNGRFNFHRGCEADITPEDLFNIFFGGGFPSGSVHSFSNGRAGYSQQHQHRHSGHEREE
  ERGDGGFSVFIQLMPIIVLILVSLLSQLMVSNPPYSLYPRSGTGQTIKMQTENLGVVYYV
  NKDFKNEYKGMLLQKVEKSVEEDYVTNIRNNCWKERQQKTDMQYAAKVYRDDRLRRKADA
  LSMDNCKELERLTSLYKGG
• Function: Acts as a co-chaperone with HSPA8/Hsc70; required to promote protein folding and trafficking, prevent aggregation of client proteins, and promote unfolded proteins to endoplasmic reticulum-associated degradation (ERAD) pathway. Acts by determining HSPA8/Hsc70's ATPase and polypeptide-binding activities. Can also act independently of HSPA8/Hsc70: together with DNAJB12, acts as a chaperone that promotes maturation of potassium channels KCND2 and KCNH2 by stabilizing nascent channel subunits and assembling them into tetramers. While stabilization of nascent channel proteins is dependent on HSPA8/Hsc70, the process of oligomerization of channel subunits is independent of HSPA8/Hsc70. When overexpressed, forms membranous structures together with DNAJB12 and HSPA8/Hsc70 within the nucleus; the role of these structures, named DJANGOs, is still unclear ; (Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection.

Molecular Interaction Atlas (MIA) of This DOT

8 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 DnaJ homolog subfamily B member 14 (DNAJB14).	[1]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of DnaJ homolog subfamily B member 14 (DNAJB14).	[2]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of DnaJ homolog subfamily B member 14 (DNAJB14).	[2]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily B member 14 (DNAJB14).	[3]
Marinol	DM70IK5	Approved	Marinol increases the expression of DnaJ homolog subfamily B member 14 (DNAJB14).	[4]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of DnaJ homolog subfamily B member 14 (DNAJB14).	[5]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DnaJ homolog subfamily B member 14 (DNAJB14).	[3]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of DnaJ homolog subfamily B member 14 (DNAJB14).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DnaJ homolog subfamily B member 14 (DNAJB14).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DnaJ homolog subfamily B member 14 (DNAJB14).	[8]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [3] 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.
• [4] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [5] 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.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [8] 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.