Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDSN5XF)

• DOT Name: Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3)
• Synonyms: EC 2.4.1.135; Beta-1,3-glucuronyltransferase 3; Glucuronosyltransferase I; GlcAT-I; UDP-GlcUA:Gal beta-1,3-Gal-R glucuronyltransferase; GlcUAT-I
• Gene Name: B3GAT3
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Craniosynostosis
  Geroderma osteodysplastica
  Larsen-like syndrome, B3GAT3 type
  Liver cancer
  Neoplasm
  Pulmonary fibrosis
  Refractive error
  Mitral valve prolapse
  Osteochondrodysplasia
  Skeletal dysplasia
  Complex neurodevelopmental disorder
  Glaucoma/ocular hypertension
• UniProt ID: B3GA3_HUMAN
• PDB ID: 1FGG; 1KWS; 3CU0
• EC Number: 2.4.1.135
• Pfam ID: PF03360
• Sequence:
  MKLKLKNVFLAYFLVSIAGLLYALVQLGQPCDCLPPLRAAAEQLRQKDLRISQLQAELRR
  PPPAPAQPPEPEALPTIYVVTPTYARLVQKAELVRLSQTLSLVPRLHWLLVEDAEGPTPL
  VSGLLAASGLLFTHLVVLTPKAQRLREGEPGWVHPRGVEQRNKALDWLRGRGGAVGGEKD
  PPPPGTQGVVYFADDDNTYSRELFEEMRWTRGVSVWPVGLVGGLRFEGPQVQDGRVVGFH
  TAWEPSRPFPVDMAGFAVALPLLLDKPNAQFDSTAPRGHLESSLLSHLVDPKDLEPRAAN
  CTRVLVWHTRTEKPKMKQEEQLQRQGRGSDPAIEV
• Function: Glycosaminoglycans biosynthesis. Involved in forming the linkage tetrasaccharide present in heparan sulfate and chondroitin sulfate. Transfers a glucuronic acid moiety from the uridine diphosphate-glucuronic acid (UDP-GlcUA) to the common linkage region trisaccharide Gal-beta-1,3-Gal-beta-1,4-Xyl covalently bound to a Ser residue at the glycosaminylglycan attachment site of proteoglycans. Can also play a role in the biosynthesis of l2/HNK-1 carbohydrate epitope on glycoproteins. Shows strict specificity for Gal-beta-1,3-Gal-beta-1,4-Xyl, exhibiting negligible incorporation into other galactoside substrates including Galbeta1-3Gal beta1-O-benzyl, Galbeta1-4GlcNAc and Galbeta1-4Glc. Stimulates 2-phosphoxylose phosphatase activity of PXYLP1 in presence of uridine diphosphate-glucuronic acid (UDP-GlcUA) during completion of linkage region formation.
• Tissue Specificity: Ubiquitous (but weakly expressed in all tissues examined).
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective B3GAT3 causes JDSSDHD (R-HSA-3560801)
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)
• BioCyc Pathway: MetaCyc:HS07624-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[1]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[2]
Geroderma osteodysplastica	DISFPJ78	Strong	Genetic Variation	[3]
Larsen-like syndrome, B3GAT3 type	DISVEUGO	Strong	Autosomal recessive	[3]
Liver cancer	DISDE4BI	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[4]
Refractive error	DISWNEQ1	Strong	Biomarker	[5]
Mitral valve prolapse	DISNCHQ3	moderate	Altered Expression	[6]
Osteochondrodysplasia	DIS9SPWW	moderate	Genetic Variation	[7]
Skeletal dysplasia	DIS5Z8U6	moderate	Genetic Variation	[7]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[8]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
UDP-glucuronic acid	DMW16X2	Investigative	Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3) affects the binding of UDP-glucuronic acid.	[19]

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 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[15]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3).	[18]

References

• [1] High Expression B3GAT3 Is Related with Poor Prognosis of Liver Cancer.Open Med (Wars). 2019 Feb 26;14:251-258. doi: 10.1515/med-2019-0020. eCollection 2019.
• [2] B3GAT3-related disorder with craniosynostosis and bone fragility due to a unique mutation.Genet Med. 2018 Feb;20(2):269-274. doi: 10.1038/gim.2017.109. Epub 2017 Aug 3.
• [3] Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes. Genes (Basel). 2019 Aug 21;10(9):631. doi: 10.3390/genes10090631.
• [4] Increased deposition of chondroitin/dermatan sulfate glycosaminoglycan and upregulation of 1,3-glucuronosyltransferase I in pulmonary fibrosis.Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L191-203. doi: 10.1152/ajplung.00214.2010. Epub 2010 Nov 5.
• [5] Corneal clouding, cataract, and colobomas with a novel missense mutation in B4GALT7-a review of eye anomalies in the linkeropathy syndromes.Am J Med Genet A. 2016 Oct;170(10):2711-8. doi: 10.1002/ajmg.a.37809. Epub 2016 Jun 20.
• [6] Faulty initiation of proteoglycan synthesis causes cardiac and joint defects. Am J Hum Genet. 2011 Jul 15;89(1):15-27. doi: 10.1016/j.ajhg.2011.05.021.
• [7] Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3.Hum Genet. 2015 Jul;134(7):691-704. doi: 10.1007/s00439-015-1549-2. Epub 2015 Apr 19.
• [8] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [9] A homozygous B3GAT3 mutation causes a severe syndrome with multiple fractures, expanding the phenotype of linkeropathy syndromes.Am J Med Genet A. 2015 Nov;167A(11):2691-6. doi: 10.1002/ajmg.a.37209. Epub 2015 Jun 18.
• [10] 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.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] The donor substrate specificity of the human beta 1,3-glucuronosyltransferase I toward UDP-glucuronic acid is determined by two crucial histidine and arginine residues. J Biol Chem. 2002 Jul 12;277(28):25439-45. doi: 10.1074/jbc.M201912200. Epub 2002 May 1.