Details of Drug Off-Target (DOT)

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

• DOT Name: Alpha-(1,3)-fucosyltransferase 4 (FUT4)
• Synonyms: 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase; EC 2.4.1.152; ELAM-1 ligand fucosyltransferase; Fucosyltransferase 4; Fucosyltransferase IV; Fuc-TIV; FucT-IV; Galactoside 3-L-fucosyltransferase
• Gene Name: FUT4
• UniProt ID: FUT4_HUMAN
• EC Number: 2.4.1.152
• Pfam ID: PF17039 ; PF00852
• Sequence:
  MRRLWGAARKPSGAGWEKEWAEAPQEAPGAWSGRLGPGRSGRKGRAVPGWASWPAHLALA
  ARPARHLGGAGQGPRPLHSGTAPFHSRASGERQRRLEPQLQHESRCRSSTPADAWRAEAA
  LPVRAMGAPWGSPTAAAGGRRGWRRGRGLPWTVCVLAAAGLTCTALITYACWGQLPPLPW
  ASPTPSRPVGVLLWWEPFGGRDSAPRPPPDCRLRFNISGCRLLTDRASYGEAQAVLFHHR
  DLVKGPPDWPPPWGIQAHTAEEVDLRVLDYEEAAAAAEALATSSPRPPGQRWVWMNFESP
  SHSPGLRSLASNLFNWTLSYRADSDVFVPYGYLYPRSHPGDPPSGLAPPLSRKQGLVAWV
  VSHWDERQARVRYYHQLSQHVTVDVFGRGGPGQPVPEIGLLHTVARYKFYLAFENSQHLD
  YITEKLWRNALLAGAVPVVLGPDRANYERFVPRGAFIHVDDFPSASSLASYLLFLDRNPA
  VYRRYFHWRRSYAVHITSFWDEPWCRVCQAVQRAGDRPKSIRNLASWFER
• Function: [Isoform Short]: Catalyzes alpha(1->3) linkage of fucosyl moiety transferred from GDP-beta-L-fucose to N-acetyl glucosamine (GlcNAc) within type 2 lactosamine (LacNAc, Gal-beta(1->4)GlcNAc) glycan attached to N- or O-linked glycoproteins. Robustly fucosylates nonsialylated distal LacNAc unit of the polylactosamine chain to form Lewis X antigen (CD15), a glycan determinant known to mediate important cellular functions in development and immunity. Fucosylates with lower efficiency sialylated LacNAc acceptors to form sialyl Lewis X and 6-sulfo sialyl Lewis X determinants that serve as recognition epitopes for C-type lectins. Together with FUT7 contributes to SELE, SELL and SELP selectin ligand biosynthesis and selectin-dependent lymphocyte homing, leukocyte migration and blood leukocyte homeostasis. In a cell type specific manner, may also fucosylate the internal LacNAc unit of the polylactosamine chain to form VIM-2 antigen that serves as recognition epitope for SELE ; [Isoform Long]: Does not generate Lewis X antigens.
• Tissue Specificity: .Expressed at low levels in bone marrow-derived mesenchymal stem cells.; Expressed in cord blood immature promyelocytes and in peripheral blood myeloid and lymphoid cell populations.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Lewis blood group biosynthesis (R-HSA-9037629)
• BioCyc Pathway: MetaCyc:HS07593-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 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 Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[8]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[2]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[15]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[16]
Ginsenoside RG3	DMFN58T	Investigative	Ginsenoside RG3 decreases the expression of Alpha-(1,3)-fucosyltransferase 4 (FUT4).	[17]

References

• [1] 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.
• [2] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [3] Upregulation of multi drug resistance genes in doxorubicin resistant human acute myelogeneous leukemia cells and reversal of the resistance. Hematology. 2007 Dec;12(6):511-7. doi: 10.1080/10245330701562535.
• [4] 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.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] Epigenetic activation of O-linked -N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia. EBioMedicine. 2020 Apr;54:102678. doi: 10.1016/j.ebiom.2020.102678. Epub 2020 Apr 6.
• [8] 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.
• [9] Heparin binding epidermal growth factor-like growth factor reduces ethanol-induced apoptosis and differentiation in human embryonic stem cells. Growth Factors. 2009 Dec;27(6):362-9. doi: 10.3109/08977190903159953.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion. Oncotarget. 2015 Jun 30;6(18):15857-70. doi: 10.18632/oncotarget.4327.
• [12] 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.
• [13] Effect of bisphenol A on human neutrophils immunophenotype. Sci Rep. 2020 Feb 20;10(1):3083. doi: 10.1038/s41598-020-59753-2.
• [14] 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.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [17] Ginsenoside Rg3 induces FUT4-mediated apoptosis in H. pylori CagA-treated gastric cancer cells by regulating SP1 and HSF1 expressions. Toxicol In Vitro. 2016 Mar;31:158-66. doi: 10.1016/j.tiv.2015.09.025. Epub 2015 Sep 30.