Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF4HBAT)

• DOT Name: Beta-1,3-galactosyltransferase 6 (B3GALT6)
• Synonyms: Beta-1,3-GalTase 6; Beta3Gal-T6; Beta3GalT6; EC 2.4.1.134; GAG GalTII; Galactosyltransferase II; Galactosylxylosylprotein 3-beta-galactosyltransferase; UDP-Gal:betaGal beta 1,3-galactosyltransferase polypeptide 6
• Gene Name: B3GALT6
• Related Disease:
  Intellectual disability
  Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures
  Connective tissue disorder
  Ehlers-Danlos syndrome
  Ehlers-Danlos syndrome, spondylodysplastic type, 1
  Ehlers-Danlos syndrome, spondylodysplastic type, 2
  Hepatocellular carcinoma
  Clear cell renal carcinoma
  Spondyloepimetaphyseal dysplasia
  Spondyloepimetaphyseal dysplasia with joint laxity
• UniProt ID: B3GT6_HUMAN
• EC Number: 2.4.1.134
• Pfam ID: PF01762
• Sequence:
  MKLLRRAWRRRAALGLGTLALCGAALLYLARCAAEPGDPRAMSGRSPPPPAPARAAAFLA
  VLVASAPRAAERRSVIRSTWLARRGAPGDVWARFAVGTAGLGAEERRALEREQARHGDLL
  LLPALRDAYENLTAKVLAMLAWLDEHVAFEFVLKADDDSFARLDALLAELRAREPARRRR
  LYWGFFSGRGRVKPGGRWREAAWQLCDYYLPYALGGGYVLSADLVHYLRLSRDYLRAWHS
  EDVSLGAWLAPVDVQREHDPRFDTEYRSRGCSNQYLVTHKQSLEDMLEKHATLAREGRLC
  KREVQLRLSYVYDWSAPPSQCCQRREGIP
• Function: Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-linked galactose residue. Has a preference for galactose-beta-1,4-xylose that is found in the linker region of glycosaminoglycans, such as heparan sulfate and chondroitin sulfate. Has no activity towards substrates with terminal glucosamine or galactosamine residues.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective B3GALT6 causes EDSP2 and SEMDJL1 (R-HSA-4420332)
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)
• BioCyc Pathway: MetaCyc:HS10991-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures	DISBUTBG	Definitive	Autosomal recessive	[2]
Connective tissue disorder	DISKXBS3	Strong	Genetic Variation	[1]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Biomarker	[3]
Ehlers-Danlos syndrome, spondylodysplastic type, 1	DISJ607K	Strong	Biomarker	[2]
Ehlers-Danlos syndrome, spondylodysplastic type, 2	DISM93ZC	Strong	Autosomal recessive	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[6]
Spondyloepimetaphyseal dysplasia	DISO4L5A	moderate	Genetic Variation	[7]
Spondyloepimetaphyseal dysplasia with joint laxity	DIS94DW9	Supportive	Autosomal recessive	[2]

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-galactosyltransferase 6 (B3GALT6).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[17]

12 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 Beta-1,3-galactosyltransferase 6 (B3GALT6).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[15]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[20]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Beta-1,3-galactosyltransferase 6 (B3GALT6).	[21]

References

• [1] Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families.Clin Genet. 2015 May;87(5):492-5. doi: 10.1111/cge.12413. Epub 2014 May 22.
• [2] Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. Am J Hum Genet. 2013 Jun 6;92(6):927-34. doi: 10.1016/j.ajhg.2013.04.003. Epub 2013 May 9.
• [3] A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the endoplasmic reticulum quality control in the mechanism of some 3GalT6-pathy mutations.Clin Genet. 2018 Jun;93(6):1148-1158. doi: 10.1111/cge.13236. Epub 2018 Mar 15.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Hepatocellular Carcinoma Detection by Plasma Methylated DNA: Discovery, Phase I Pilot, and Phase II Clinical Validation.Hepatology. 2019 Mar;69(3):1180-1192. doi: 10.1002/hep.30244. Epub 2019 Feb 5.
• [6] Beta-1,4-galactosyltransferase II predicts poor prognosis of patients with non-metastatic clear-cell renal cell carcinoma.Tumour Biol. 2017 Feb;39(2):1010428317691417. doi: 10.1177/1010428317691417.
• [7] Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome. Hum Mol Genet. 2018 Oct 15;27(20):3475-3487. doi: 10.1093/hmg/ddy234.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] 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.
• [19] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [21] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.