Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXQ6P8R)

• DOT Name: 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3)
• Synonyms: EC 2.4.1.65; 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase; EC 2.4.1.152; Alpha-3-fucosyltransferase FUT3; EC 2.4.1.-; Blood group Lewis alpha-4-fucosyltransferase; Lewis FT; Fucosyltransferase 3; Fucosyltransferase III; FucT-III
• Gene Name: FUT3
• UniProt ID: FUT3_HUMAN
• EC Number: 2.4.1.-; 2.4.1.152; 2.4.1.65
• Pfam ID: PF17039 ; PF00852
• Sequence:
  MDPLGAAKPQWPWRRCLAALLFQLLVAVCFFSYLRVSRDDATGSPRAPSGSSRQDTTPTR
  PTLLILLRTWPFHIPVALSRCSEMVPGTADCHITADRKVYPQADMVIVHHWDIMSNPKSR
  LPPSPRPQGQRWIWFNLEPPPNCQHLEALDRYFNLTMSYRSDSDIFTPYGWLEPWSGQPA
  HPPLNLSAKTELVAWAVSNWKPDSARVRYYQSLQAHLKVDVYGRSHKPLPKGTMMETLSR
  YKFYLAFENSLHPDYITEKLWRNALEAWAVPVVLGPSRSNYERFLPPDAFIHVDDFQSPK
  DLARYLQELDKDHARYLSYFRWRETLRPRSFSWALDFCKACWKLQQESRYQTVRSIAAWF
  T
• Function: Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to both the subterminal N-acetyl glucosamine (GlcNAc) of type 1 chain (beta-D-Gal-(1->3)-beta-D-GlcNAc) glycolipids and oligosaccharides via an alpha(1,4) linkage, and the subterminal glucose (Glc) or GlcNAc of type 2 chain (beta-D-Gal-(1->4)-beta-D-GlcNAc) oligosaccharides via an alpha(1,3) linkage, independently of the presence of terminal alpha-L-fucosyl-(1,2) moieties on the terminal galactose of these acceptors. Through its catalytic activity, participates in the synthesis of antigens of the Lewis blood group system, i.e. Lewis a (Le(a)), lewis b (Le(b)), Lewis x/SSEA-1 (Le(x)) and lewis y (Le(y)) antigens. Also catalyzes the transfer of L-fucose to subterminal GlcNAc of sialyl- and disialyl-lactotetraosylceramide to produce sialyl Lewis a (sLe(a)) and disialyl Lewis a via an alpha(1,4) linkage and therefore may regulate cell surface sLe(a) expression and consequently regulates adhesive properties to E-selectin, cell proliferation and migration. Catalyzes the transfer of an L-fucose to 3'-sialyl-N-acetyllactosamine by an alpha(1,3) linkage, which allows the formation of sialyl-Lewis x structure and therefore may regulate the sialyl-Lewis x surface antigen expression and consequently adhesive properties to E-selectin. Prefers type 1 chain over type 2 acceptors. Type 1 tetrasaccharide is a better acceptor than type 1 disaccharide suggesting that a beta anomeric configuration of GlcNAc in the substrate is preferred. Lewis-positive (Le(+)) individuals have an active enzyme while Lewis-negative (Le(-)) individuals have an inactive enzyme.
• Tissue Specificity: Highly expressed in stomach, colon, small intestine, lung and kidney and to a lesser extent in salivary gland, bladder, uterus and liver.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Reactions specific to the complex N-glycan synthesis pathway (R-HSA-975578)
  Lewis blood group biosynthesis (R-HSA-9037629)
• BioCyc Pathway: MetaCyc:HS10249-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3) decreases the response to substance of Arsenic trioxide.	[11]

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 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[3]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[4]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[2]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 (FUT3).	[10]

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] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [3] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [4] Expression of Lea in gastric cancer cell lines depends on FUT3 expression regulated by promoter methylation. Cancer Lett. 2006 Oct 28;242(2):191-7. doi: 10.1016/j.canlet.2005.11.009. Epub 2006 Jan 19.
• [5] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [6] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.