Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT0KEZR)

• DOT Name: Prolactin regulatory element-binding protein (PREB)
• Synonyms: Mammalian guanine nucleotide exchange factor mSec12
• Gene Name: PREB
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: PREB_HUMAN
• PDB ID: 5TF2
• Pfam ID: PF00400
• Sequence:
  MGRRRAPELYRAPFPLYALQVDPSTGLLIAAGGGGAAKTGIKNGVHFLQLELINGRLSAS
  LLHSHDTETRATMNLALAGDILAAGQDAHCQLLRFQAHQQQGNKAEKAGSKEQGPRQRKG
  AAPAEKKCGAETQHEGLELRVENLQAVQTDFSSDPLQKVVCFNHDNTLLATGGTDGYVRV
  WKVPSLEKVLEFKAHEGEIEDLALGPDGKLVTVGRDLKASVWQKDQLVTQLHWQENGPTF
  SSTPYRYQACRFGQVPDQPAGLRLFTVQIPHKRLRQPPPCYLTAWDGSNFLPLRTKSCGH
  EVVSCLDVSESGTFLGLGTVTGSVAIYIAFSLQCLYYVREAHGIVVTDVAFLPEKGRGPE
  LLGSHETALFSVAVDSRCQLHLLPSRRSVPVWLLLLLCVGLIIVTILLLQSAFPGFL
• Function: Guanine nucleotide exchange factor that specifically activates the small GTPase SAR1B. Mediates the recruitment of SAR1B and other COPII coat components to endoplasmic reticulum membranes and is therefore required for the formation of COPII transport vesicles from the ER; Was first identified based on its probable role in the regulation of pituitary gene transcription. Binds to the prolactin gene (PRL) promoter and seems to activate transcription.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Cargo concentration in the ER (R-HSA-5694530)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Prolactin regulatory element-binding protein (PREB).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Prolactin regulatory element-binding protein (PREB).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prolactin regulatory element-binding protein (PREB).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Prolactin regulatory element-binding protein (PREB).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Prolactin regulatory element-binding protein (PREB).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolactin regulatory element-binding protein (PREB).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Prolactin regulatory element-binding protein (PREB).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Prolactin regulatory element-binding protein (PREB).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Prolactin regulatory element-binding protein (PREB).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prolactin regulatory element-binding protein (PREB).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Prolactin regulatory element-binding protein (PREB).	[12]

References

• [1] Prolactin regulatory element-binding (PREB) protein regulates hepatic glucose homeostasis.Biochim Biophys Acta Mol Basis Dis. 2018 Jun;1864(6 Pt A):2097-2107. doi: 10.1016/j.bbadis.2018.03.024. Epub 2018 Mar 28.
• [2] 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.
• [3] 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.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [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] 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.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.