Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHMZY12)

• DOT Name: Beta-1,4-galactosyltransferase 5 (B4GALT5)
• Synonyms: Beta-1,4-GalTase 5; Beta4Gal-T5; b4Gal-T5; EC 2.4.1.-; Beta-1,4-GalT II; Glucosylceramide beta-1,4-galactosyltransferase; EC 2.4.1.274; Lactosylceramide synthase; LacCer synthase; UDP-Gal:beta-GlcNAc beta-1,4-galactosyltransferase 5; UDP-galactose:beta-N-acetylglucosamine beta-1,4-galactosyltransferase 5
• Gene Name: B4GALT5
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Glioma
  Juvenile idiopathic arthritis
  Neoplasm
  Obesity
  Type-1/2 diabetes
• UniProt ID: B4GT5_HUMAN
• EC Number: 2.4.1.-; 2.4.1.274
• Pfam ID: PF02709 ; PF13733
• Sequence:
  MRARRGLLRLPRRSLLAALFFFSLSSSLLYFVYVAPGIVNTYLFMMQAQGILIRDNVRTI
  GAQVYEQVLRSAYAKRNSSVNDSDYPLDLNHSETFLQTTTFLPEDFTYFANHTCPERLPS
  MKGPIDINMSEIGMDYIHELFSKDPTIKLGGHWKPSDCMPRWKVAILIPFRNRHEHLPVL
  FRHLLPMLQRQRLQFAFYVVEQVGTQPFNRAMLFNVGFQEAMKDLDWDCLIFHDVDHIPE
  SDRNYYGCGQMPRHFATKLDKYMYLLPYTEFFGGVSGLTVEQFRKINGFPNAFWGWGGED
  DDLWNRVQNAGYSVSRPEGDTGKYKSIPHHHRGEVQFLGRYALLRKSKERQGLDGLNNLN
  YFANITYDALYKNITVNLTPELAQVNEY
• Function: Catalyzes the synthesis of lactosylceramide (LacCer) via the transfer of galactose from UDP-galactose to glucosylceramide (GlcCer). LacCer is the starting point in the biosynthesis of all gangliosides (membrane-bound glycosphingolipids) which play pivotal roles in the CNS including neuronal maturation and axonal and myelin formation. Plays a role in the glycosylation of BMPR1A and regulation of its protein stability. Essential for extraembryonic development during early embryogenesis.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  O-linked glycosylation of mucins (R-HSA-913709)
  N-Glycan antennae elongation (R-HSA-975577)
  Keratan sulfate biosynthesis (R-HSA-2022854)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Obesity	DIS47Y1K	moderate	Altered Expression	[6]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[6]

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 Beta-1,4-galactosyltransferase 5 (B4GALT5).	[7]

11 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-1,4-galactosyltransferase 5 (B4GALT5).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[14]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Beta-1,4-galactosyltransferase 5 (B4GALT5).	[18]

References

• [1] Correlated gene expression between beta-1,4-galactosyltransferase V and N-acetylglucosaminyltransferase V in human cancer cell lines.Biochem Biophys Res Commun. 2000 Oct 5;276(3):1019-23. doi: 10.1006/bbrc.2000.3594.
• [2] Lactosylceramide synthase -1,4-GalT-V: A novel target for the diagnosis and therapy of human colorectal cancer.Biochem Biophys Res Commun. 2019 Jan 8;508(2):380-386. doi: 10.1016/j.bbrc.2018.11.149. Epub 2018 Nov 28.
• [3] 1,4-Galactosyltransferase V activates Notch1 signaling in glioma stem-like cells and promotes their transdifferentiation into endothelial cells.J Biol Chem. 2018 Feb 9;293(6):2219-2230. doi: 10.1074/jbc.RA117.000682. Epub 2017 Dec 21.
• [4] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [5] The Immunological Regulation Roles of Porcine -1, 4 Galactosyltransferase V (B4GALT5) in PRRSV Infection.Front Cell Infect Microbiol. 2018 Mar 1;8:48. doi: 10.3389/fcimb.2018.00048. eCollection 2018.
• [6] Downregulation of 1,4-galactosyltransferase 5 improves insulin resistance by promoting adipocyte commitment and reducing inflammation.Cell Death Dis. 2018 Feb 7;9(2):196. doi: 10.1038/s41419-017-0239-5.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Galactomutarotase and other galactose-related genes are rapidly induced by retinoic acid in human myeloid cells. Biochemistry. 2007 Dec 25;46(51):15198-207. doi: 10.1021/bi701891t. Epub 2007 Dec 4.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Down-regulation of beta1,4GalT V at protein level contributes to arsenic trioxide-induced glioma cell apoptosis. Cancer Lett. 2008 Aug 18;267(1):96-105. doi: 10.1016/j.canlet.2008.03.019. Epub 2008 Apr 24.
• [15] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.