Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHZ25Y8)

• DOT Name: ERO1-like protein beta (ERO1B)
• Synonyms: ERO1-L-beta; EC 1.8.4.-; Endoplasmic reticulum oxidoreductase beta; Endoplasmic reticulum oxidoreductin-1-like protein B; Oxidoreductin-1-L-beta
• Gene Name: ERO1B
• Related Disease:
  Pancreatic cancer
  Asthma
• UniProt ID: ERO1B_HUMAN
• EC Number: 1.8.4.-
• Pfam ID: PF04137
• Sequence:
  MSQGVRRAGAGQGVAAAVQLLVTLSFLRSVVEAQVTGVLDDCLCDIDSIDNFNTYKIFPK
  IKKLQERDYFRYYKVNLKRPCPFWAEDGHCSIKDCHVEPCPESKIPVGIKAGHSNKYLKM
  ANNTKELEDCEQANKLGAINSTLSNQSKEAFIDWARYDDSRDHFCELDDERSPAAQYVDL
  LLNPERYTGYKGTSAWRVWNSIYEENCFKPRSVYRPLNPLAPSRGEDDGESFYTWLEGLC
  LEKRVFYKLISGLHASINLHLCANYLLEETWGKPSWGPNIKEFKHRFDPVETKGEGPRRL
  KNLYFLYLIELRALSKVAPYFERSIVDLYTGNAEEDADTKTLLLNIFQDTKSFPMHFDEK
  SMFAGDKKGAKSLKEEFRLHFKNISRIMDCVGCDKCRLWGKLQTQGLGTALKILFSEKEI
  QKLPENSPSKGFQLTRQEIVALLNAFGRLSTSIRDLQNFKVLLQHSR
• Function: Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Other protein disulfide isomerase family members can also be reoxidized, but at lower rates compared to P4HB, including PDIA2 (50% of P4HB reoxidation rate), as well as PDIA3, PDIA4, PDIA6 and NXNDC12 (<10%). Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. May be involved in oxidative proinsulin folding in pancreatic cells, hence may play a role in glucose homeostasis.
• Tissue Specificity: Highly expressed in the digestive tract, including the duodenum and lower digestive tract. In the stomach, highly expressed in enzyme-producing chief cells (at protein level). In the pancreas, expressed in islets of Langerhans and, at lower levels, in enzyme-secreting cells (at protein level). Detected at low level in many other tissues.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: Insulin processing (R-HSA-264876)
• BioCyc Pathway: MetaCyc:ENSG00000086619-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pancreatic cancer	DISJC981	Strong	Biomarker	[1]
Asthma	DISW9QNS	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of ERO1-like protein beta (ERO1B).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ERO1-like protein beta (ERO1B).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ERO1-like protein beta (ERO1B).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ERO1-like protein beta (ERO1B).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ERO1-like protein beta (ERO1B).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ERO1-like protein beta (ERO1B).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ERO1-like protein beta (ERO1B).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of ERO1-like protein beta (ERO1B).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ERO1-like protein beta (ERO1B).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ERO1-like protein beta (ERO1B).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ERO1-like protein beta (ERO1B).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ERO1-like protein beta (ERO1B).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ERO1-like protein beta (ERO1B).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ERO1-like protein beta (ERO1B).	[16]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of ERO1-like protein beta (ERO1B).	[17]

References

• [1] Genome-scale analysis identifies GJB2 and ERO1LB as prognosis markers in patients with pancreatic cancer.Oncotarget. 2017 Mar 28;8(13):21281-21289. doi: 10.18632/oncotarget.15068.
• [2] A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.J Allergy Clin Immunol. 2008 Apr;121(4):860-3. doi: 10.1016/j.jaci.2008.01.015.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [10] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] 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.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.