Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0DE43)

• DOT Name: Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5)
• Synonyms: EC 2.4.1.206; Lactotriaosylceramide synthase; Lc(3)Cer synthase; Lc3 synthase; UDP-GlcNAc:beta-Gal beta-1,3-N-acetylglucosaminyltransferase 5; BGnT-5; Beta-1,3-Gn-T5; Beta-1,3-N-acetylglucosaminyltransferase 5; Beta3Gn-T5
• Gene Name: B3GNT5
• Related Disease:
  Breast neoplasm
  Glioblastoma multiforme
• UniProt ID: B3GN5_HUMAN
• EC Number: 2.4.1.206
• Pfam ID: PF01762
• Sequence:
  MRMLVSGRRVKKWQLIIQLFATCFLASLMFFWEPIDNHIVSHMKSYSYRYLINSYDFVND
  TLSLKHTSAGPRYQYLINHKEKCQAQDVLLLLFVKTAPENYDRRSGIRRTWGNENYVRSQ
  LNANIKTLFALGTPNPLEGEELQRKLAWEDQRYNDIIQQDFVDSFYNLTLKLLMQFSWAN
  TYCPHAKFLMTADDDIFIHMPNLIEYLQSLEQIGVQDFWIGRVHRGAPPIRDKSSKYYVS
  YEMYQWPAYPDYTAGAAYVISGDVAAKVYEASQTLNSSLYIDDVFMGLCANKIGIVPQDH
  VFFSGEGKTPYHPCIYEKMMTSHGHLEDLQDLWKNATDPKVKTISKGFFGQIYCRLMKII
  LLCKISYVDTYPCRAAFI
• Function: Beta-1,3-N-acetylglucosaminyltransferase that plays a key role in the synthesis of lacto- or neolacto-series carbohydrate chains on glycolipids, notably by participating in biosynthesis of HNK-1 and Lewis X carbohydrate structures. Has strong activity toward lactosylceramide (LacCer) and neolactotetraosylceramide (nLc(4)Cer; paragloboside), resulting in the synthesis of Lc(3)Cer and neolactopentaosylceramide (nLc(5)Cer), respectively. Probably plays a central role in regulating neolacto-series glycolipid synthesis during embryonic development.
• Tissue Specificity: Widely expressed. Highly expressed in lung, colon, placenta, testis, pituitary gland and cerebellum. Weakly expressed in brain, liver, spleen, lymph node and thymus.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• Reactome Pathway: O-linked glycosylation of mucins (R-HSA-913709)
• BioCyc Pathway: MetaCyc:ENSG00000176597-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[12]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[13]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[8]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase (B3GNT5).	[18]

References

• [1] Glycan-related gene expression signatures in breast cancer subtypes; relation to survival.Mol Oncol. 2015 Apr;9(4):861-76. doi: 10.1016/j.molonc.2014.12.013. Epub 2015 Jan 14.
• [2] DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC Genomics. 2010 Dec 14;11:701.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] 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.
• [11] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [14] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] 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.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.