Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBZUQ7F)

• DOT Name: 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6)
• Synonyms: EC 2.4.1.152; Fucosyltransferase 6; Fucosyltransferase VI; Fuc-TVI; FucT-VI; Galactoside 3-L-fucosyltransferase
• Gene Name: FUT6
• Related Disease:
  Hepatocellular carcinoma
  Acute myelogenous leukaemia
  Advanced cancer
  Age-related macular degeneration
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Gastric cancer
  Herpes simplex infection
  Neoplasm
  Neovascular age-related macular degeneration
  Pernicious anemia
  Stomach cancer
  Colon adenocarcinoma
  Colorectal carcinoma
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate carcinoma
  Fucosyltransferase 6 deficiency
• UniProt ID: FUT6_HUMAN
• EC Number: 2.4.1.152
• Pfam ID: PF17039 ; PF00852
• Sequence:
  MDPLGPAKPQWSWRCCLTTLLFQLLMAVCFFSYLRVSQDDPTVYPNGSRFPDSTGTPAHS
  IPLILLWTWPFNKPIALPRCSEMVPGTADCNITADRKVYPQADAVIVHHREVMYNPSAQL
  PRSPRRQGQRWIWFSMESPSHCWQLKAMDGYFNLTMSYRSDSDIFTPYGWLEPWSGQPAH
  PPLNLSAKTELVAWAVSNWGPNSARVRYYQSLQAHLKVDVYGRSHKPLPQGTMMETLSRY
  KFYLAFENSLHPDYITEKLWRNALEAWAVPVVLGPSRSNYERFLPPDAFIHVDDFQSPKD
  LARYLQELDKDHARYLSYFRWRETLRPRSFSWALAFCKACWKLQEESRYQTRGIAAWFT
• Function: [Isoform 1]: Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the N-acetyl glucosamine (GlcNAc) of a distal alpha2,3 sialylated lactosamine unit of a glycoprotein- or a glycolipid-linked sialopolylactosamines chain or of a distal or internal lactosamine unit of a neutral glycoprotein- or a glycolipid-linked polylactosamines chain through an alpha-1,3 glycosidic linkage and participates in surface expression of the sialyl Lewis X (sLe(x)), Lewis X (Le(x)) and non sialylated VIM2 determinants. Moreover transfers fucose to H-type 2 (Fucalpha1-2Galbeta1-4GlcNAc) chain acceptor substrates and participates in difucosylated sialyl Lewis x determinants. Also fucosylates a polylactosamine substrate having a 6 sulfate modification at the GlcNAc moiety and gives rise to sialyl and non-sialyl 6-sulfo lewis X. Does not have activity towards type 1 ((Galbeta1-3GlcNAc)) and H-type 1 chain (Fucalpha1-2Galbeta1-3GlcNAc) acceptors substrates ; [Isoform 2]: Does not have alpha(1,3)-fucosyltransferase activity.
• Tissue Specificity: Kidney, liver, colon, small intestine, bladder, uterus and salivary gland.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Lewis blood group biosynthesis (R-HSA-9037629)
• BioCyc Pathway: MetaCyc:HS08124-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[4]
Pernicious anemia	DISWV404	Strong	Genetic Variation	[9]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[12]
Prostate cancer	DISF190Y	Limited	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[13]
Fucosyltransferase 6 deficiency	DISXIFYV	No Known	Autosomal recessive	[14]

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 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[15]

10 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 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[20]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[21]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 (FUT6).	[23]

References

• [1] FUT family mediates the multidrug resistance of human hepatocellular carcinoma via the PI3K/Akt signaling pathway.Cell Death Dis. 2013 Nov 14;4(11):e923. doi: 10.1038/cddis.2013.450.
• [2] Prognostic value of the FUT family in acute myeloid leukemia.Cancer Gene Ther. 2020 Feb;27(1-2):70-80. doi: 10.1038/s41417-019-0115-9. Epub 2019 Jun 17.
• [3] Fucosylated TGF- receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells.Br J Cancer. 2014 Jan 7;110(1):156-63. doi: 10.1038/bjc.2013.699. Epub 2013 Nov 19.
• [4] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [5] MicroRNA-106b targets FUT6 to promote cell migration, invasion, and proliferation in human breast cancer.IUBMB Life. 2016 Sep;68(9):764-75. doi: 10.1002/iub.1541. Epub 2016 Aug 13.
• [6] The biosynthesis of the selectin-ligand sialyl Lewis x in colorectal cancer tissues is regulated by fucosyltransferase VI and can be inhibited by an RNA interference-based approach.Int J Biochem Cell Biol. 2011 Jan;43(1):130-9. doi: 10.1016/j.biocel.2010.10.004. Epub 2010 Oct 19.
• [7] Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population.Int J Cancer. 2015 Feb 15;136(4):880-93. doi: 10.1002/ijc.29034. Epub 2014 Jul 1.
• [8] NFB-mediated activation of the cellular FUT3, 5 and 6 gene cluster by herpes simplex virus type 1.Glycobiology. 2017 Nov 1;27(11):999-1005. doi: 10.1093/glycob/cwx079.
• [9] Single nucleotide polymorphisms related to vitamin B12 serum levels in autoimmune gastritis patients with or without pernicious anaemia.Dig Liver Dis. 2015 Apr;47(4):285-90. doi: 10.1016/j.dld.2015.01.147. Epub 2015 Jan 22.
• [10] Death receptor 5 is activated by fucosylation in colon cancer cells.FEBS J. 2019 Feb;286(3):555-571. doi: 10.1111/febs.14742. Epub 2019 Jan 14.
• [11] HOTAIR/miR-326/FUT6 axis facilitates colorectal cancer progression through regulating fucosylation of CD44 via PI3K/AKT/mTOR pathway.Biochim Biophys Acta Mol Cell Res. 2019 May;1866(5):750-760. doi: 10.1016/j.bbamcr.2019.02.004. Epub 2019 Feb 8.
• [12] The Uyghur population and genetic susceptibility to type 2 diabetes: potential role for variants in CAPN10, APM1 and FUT6 genes.J Cell Mol Med. 2016 Nov;20(11):2138-2147. doi: 10.1111/jcmm.12911. Epub 2016 Jul 4.
• [13] Human fucosyltransferase 6 enables prostate cancer metastasis to bone.Br J Cancer. 2013 Dec 10;109(12):3014-22. doi: 10.1038/bjc.2013.690. Epub 2013 Oct 31.
• [14] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] 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.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.