Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWAN10O)

• DOT Name: Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG)
• Synonyms: EC 2.4.1.222; O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase
• Gene Name: RFNG
• UniProt ID: RFNG_HUMAN
• EC Number: 2.4.1.222
• Pfam ID: PF02434
• Sequence:
  MSRARGALCRACLALAAALAALLLLPLPLPRAPAPARTPAPAPRAPPSRPAAPSLRPDDV
  FIAVKTTRKNHGPRLRLLLRTWISRARQQTFIFTDGDDPELELQGGDRVINTNCSAVRTR
  QALCCKMSVEYDKFIESGRKWFCHVDDDNYVNARSLLHLLSSFSPSQDVYLGRPSLDHPI
  EATERVQGGRTVTTVKFWFATGGAGFCLSRGLALKMSPWASLGSFMSTAEQVRLPDDCTV
  GYIVEGLLGARLLHSPLFHSHLENLQRLPPDTLLQQVTLSHGGPENPHNVVNVAGGFSLH
  QDPTRFKSIHCLLYPDTDWCPRQKQGAPTSR
• Function: Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. Modulates NOTCH1 activity by modifying O-fucose residues at specific EGF-like domains resulting in enhancement of NOTCH1 activation by DLL1 and JAG1. May be involved in limb formation and in neurogenesis.
• KEGG Pathway:
  Other types of O-glycan biosynthesis (hsa00514)
  Notch sig.ling pathway (hsa04330)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway: Pre-NOTCH Processing in Golgi (R-HSA-1912420)

Molecular Interaction Atlas (MIA) of This DOT

2 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 Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[3]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[8]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Beta-1,3-N-acetylglucosaminyltransferase radical fringe (RFNG).	[9]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [8] 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.
• [9] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.