Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5NH9TD)

• DOT Name: Beta-1,4-glucuronyltransferase 1 (B4GAT1)
• Synonyms: EC 2.4.1.-; I-beta-1,3-N-acetylglucosaminyltransferase; iGnT; N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase; Poly-N-acetyllactosamine extension enzyme; UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 1
• Gene Name: B4GAT1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Central core myopathy
  Ciliopathy
  Congenital fiber-type disproportion myopathy
  Congenital myopathy
  Limb-girdle muscular dystrophy due to POMK deficiency
  Multiminicore myopathy
  Muscular dystrophy
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
  Nemaline myopathy
  Muscular dystrophy-dystroglycanopathy, type A
• UniProt ID: B4GA1_HUMAN
• EC Number: 2.4.1.-
• Pfam ID: PF13896
• Sequence:
  MQMSYAIRCAFYQLLLAALMLVAMLQLLYLSLLSGLHGQEEQDQYFEFFPPSPRSVDQVK
  AQLRTALASGGVLDASGDYRVYRGLLKTTMDPNDVILATHASVDNLLHLSGLLERWEGPL
  SVSVFAATKEEAQLATVLAYALSSHCPDMRARVAMHLVCPSRYEAAVPDPREPGEFALLR
  SCQEVFDKLARVAQPGINYALGTNVSYPNNLLRNLAREGANYALVIDVDMVPSEGLWRGL
  REMLDQSNQWGGTALVVPAFEIRRARRMPMNKNELVQLYQVGEVRPFYYGLCTPCQAPTN
  YSRWVNLPEESLLRPAYVVPWQDPWEPFYVAGGKVPTFDERFRQYGFNRISQACELHVAG
  FDFEVLNEGFLVHKGFKEALKFHPQKEAENQHNKILYRQFKQELKAKYPNSPRRC
• Function: Beta-1,4-glucuronyltransferase involved in O-mannosylation of alpha-dystroglycan (DAG1). Transfers a glucuronic acid (GlcA) residue onto a xylose (Xyl) acceptor to produce the glucuronyl-beta-1,4-xylose-beta disaccharide primer, which is further elongated by LARGE1, during synthesis of phosphorylated O-mannosyl glycan. Phosphorylated O-mannosyl glycan is a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity. Required for axon guidance; via its function in O-mannosylation of alpha-dystroglycan (DAG1).
• Tissue Specificity: In the adult, highly expressed in heart, brain, skeletal muscle and kidney and to a lesser extent in placenta, pancreas, spleen, prostate, testis, ovary, small intestine and colon. Very weak expression in lung, liver, thymus and peripheral blood leukocytes. In fetal highly expressed in brain and kidney and to a lesser extent in lung and liver.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective LARGE causes MDDGA6 and MDDGB6 (R-HSA-5083627)
  O-linked glycosylation (R-HSA-5173105)
  Keratan sulfate biosynthesis (R-HSA-2022854)
• BioCyc Pathway: MetaCyc:HS10821-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Central core myopathy	DIS18AZZ	Strong	Biomarker	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[3]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Biomarker	[2]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[2]
Limb-girdle muscular dystrophy due to POMK deficiency	DISM63SY	Strong	Biomarker	[2]
Multiminicore myopathy	DISE6VYN	Strong	Biomarker	[2]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[4]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A13	DISZMV14	Strong	Autosomal recessive	[5]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	DIS2BGID	Strong	Biomarker	[2]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	DISSP7OL	Strong	Biomarker	[2]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[2]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[5]

10 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 Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[12]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Beta-1,4-glucuronyltransferase 1 (B4GAT1).	[15]

References

• [1] A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.
• [2] Dystroglycan organizes axon guidance cue localization and axonal pathfinding.Neuron. 2012 Dec 6;76(5):931-44. doi: 10.1016/j.neuron.2012.10.009.
• [3] Accelerating Gene Discovery by Phenotyping Whole-Genome Sequenced Multi-mutation Strains and Using the Sequence Kernel Association Test (SKAT).PLoS Genet. 2016 Aug 10;12(8):e1006235. doi: 10.1371/journal.pgen.1006235. eCollection 2016 Aug.
• [4] Integrative data mining highlights candidate genes for monogenic myopathies.PLoS One. 2014 Oct 29;9(10):e110888. doi: 10.1371/journal.pone.0110888. eCollection 2014.
• [5] Missense mutations in -1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome. Hum Mol Genet. 2013 May 1;22(9):1746-54. doi: 10.1093/hmg/ddt021. Epub 2013 Jan 28.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [14] 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.
• [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.