Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJF6BSN)

• DOT Name: Alpha-(1,3)-fucosyltransferase 7 (FUT7)
• Synonyms: EC 2.4.1.-; Fucosyltransferase 7; Fucosyltransferase VII; Fuc-TVII; FucT-VII; Galactoside 3-L-fucosyltransferase; Selectin ligand synthase
• Gene Name: FUT7
• Related Disease:
  Acute myelogenous leukaemia
  Arteriosclerosis
  Atherosclerosis
  Colon cancer
  Colon carcinoma
  Dermatitis
  Hepatocellular carcinoma
  Lung cancer
  Myocardial infarction
  Neoplasm
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate carcinoma
  Retinoblastoma
  Lung carcinoma
  OPTN-related open angle glaucoma
  Colon adenocarcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Metastatic malignant neoplasm
  Nervous system inflammation
• UniProt ID: FUT7_HUMAN
• EC Number: 2.4.1.-
• Pfam ID: PF17039 ; PF00852
• Sequence:
  MNNAGHGPTRRLRGLGVLAGVALLAALWLLWLLGSAPRGTPAPQPTITILVWHWPFTDQP
  PELPSDTCTRYGIARCHLSANRSLLASADAVVFHHRELQTRRSHLPLAQRPRGQPWVWAS
  MESPSHTHGLSHLRGIFNWVLSYRRDSDIFVPYGRLEPHWGPSPPLPAKSRVAAWVVSNF
  QERQLRARLYRQLAPHLRVDVFGRANGRPLCASCLVPTVAQYRFYLSFENSQHRDYITEK
  FWRNALVAGTVPVVLGPPRATYEAFVPADAFVHVDDFGSARELAAFLTGMNESRYQRFFA
  WRDRLRVRLFTDWRERFCAICDRYPHLPRSQVYEDLEGWFQA
• Function: 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 through an alpha-1,3 glycosidic linkage and participates in the final fucosylation step in the biosynthesis of the sialyl Lewis X (sLe(x)), a carbohydrate involved in cell and matrix adhesion during leukocyte trafficking and fertilization. In vitro, also synthesizes sialyl-dimeric-Lex structures, from VIM-2 structures and both di-fucosylated and trifucosylated structures from mono-fucosylated precursors. However does not catalyze alpha 1-3 fucosylation when an internal alpha 1-3 fucosylation is present in polylactosamine chain and the fucosylation rate of the internal GlcNAc residues is reduced once fucose has been added to the distal GlcNAc. Also catalyzes the transfer of a fucose from GDP-beta-fucose to the 6-sulfated a(2,3)sialylated substrate to produce 6-sulfo sLex mediating significant L-selectin-dependent cell adhesion. Through sialyl-Lewis(x) biosynthesis, can control SELE- and SELP-mediated cell adhesion with leukocytes and allows leukocytes tethering and rolling along the endothelial tissue thereby enabling the leukocytes to accumulate at a site of inflammation. May enhance embryo implantation through sialyl Lewis X (sLeX)-mediated adhesion of embryo cells to endometrium. May affect insulin signaling by up-regulating the phosphorylation and expression of some signaling molecules involved in the insulin-signaling pathway through SLe(x) which is present on the glycans of the INSRR alpha subunit.
• Tissue Specificity: Leukocytic/myeloid lineage cells.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Lewis blood group biosynthesis (R-HSA-9037629)
• BioCyc Pathway: MetaCyc:HS11506-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Dermatitis	DISY5SZC	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[9]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[10]
Lung carcinoma	DISTR26C	moderate	Biomarker	[11]
OPTN-related open angle glaucoma	DISDR98A	Disputed	Genetic Variation	[12]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[13]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[14]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[14]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[14]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[15]

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 Alpha-(1,3)-fucosyltransferase 7 (FUT7).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Alpha-(1,3)-fucosyltransferase 7 (FUT7).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Alpha-(1,3)-fucosyltransferase 7 (FUT7).	[18]
Pantothenic acid	DM091H2	Approved	Pantothenic acid decreases the expression of Alpha-(1,3)-fucosyltransferase 7 (FUT7).	[19]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Alpha-(1,3)-fucosyltransferase 7 (FUT7).	[18]

References

• [1] Effect of ST3GAL 4 and FUT 7 on sialyl Lewis X synthesis and multidrug resistance in human acute myeloid leukemia.Biochim Biophys Acta. 2014 Sep;1842(9):1681-92. doi: 10.1016/j.bbadis.2014.06.014. Epub 2014 Jun 19.
• [2] The 1,3-fucosyltransferase FUT7 regulates IL-1-induced monocyte-endothelial adhesion via fucosylation of endomucin.Life Sci. 2018 Jan 1;192:231-237. doi: 10.1016/j.lfs.2017.11.017. Epub 2017 Nov 11.
• [3] 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.
• [4] Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene.J Immunol. 2016 Oct 15;197(8):3406-3414. doi: 10.4049/jimmunol.1502434. Epub 2016 Sep 2.
• [5] -1,3-Fucosyltransferase-VII siRNA inhibits the expression of SLex and hepatocarcinoma cell proliferation.Int J Mol Med. 2018 Nov;42(5):2700-2708. doi: 10.3892/ijmm.2018.3850. Epub 2018 Aug 31.
• [6] Expression of alpha-1,3-fucosyltransferase type IV and VII genes is related to poor prognosis in lung cancer.Cancer Res. 1996 Jan 15;56(2):325-9.
• [7] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [8] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [9] Knockdown of fucosyltransferase III disrupts the adhesion of circulating cancer cells to E-selectin without affecting hematopoietic cell adhesion.Carbohydr Res. 2010 Nov 2;345(16):2334-42. doi: 10.1016/j.carres.2010.07.028. Epub 2010 Jul 21.
• [10] alpha-1,3-Fucosyltransferase-VII stimulates the growth of hepatocarcinoma cells via the cyclin-dependent kinase inhibitor p27Kip1.Cell Mol Life Sci. 2005 Jan;62(2):171-8. doi: 10.1007/s00018-004-4349-8.
• [11] alpha-2,3-Sialyltransferase type 3N and alpha-1,3-fucosyltransferase type VII are related to sialyl Lewis(x) synthesis and patient survival from lung carcinoma.Cancer. 1997 May 1;79(9):1678-85. doi: 10.1002/(sici)1097-0142(19970501)79:9<1678::aid-cncr7>3.0.co;2-8.
• [12] Family-based analysis identified CD2 as a susceptibility gene for primary open angle glaucoma in Chinese Han population.J Cell Mol Med. 2014 Apr;18(4):600-9. doi: 10.1111/jcmm.12201. Epub 2014 Mar 6.
• [13] Elevation of an alpha(1,3)fucosyltransferase activity correlated with apoptosis in the human colon adenocarcinoma cell line, HT-29.Glycoconj J. 1996 Dec;13(6):1021-9. doi: 10.1007/BF01053198.
• [14] Alpha1,3 fucosyltransferase VII plays a role in colorectal carcinoma metastases by promoting the carbohydration of glycoprotein CD24.Oncol Rep. 2010 Jun;23(6):1609-17. doi: 10.3892/or_00000802.
• [15] Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII.J Immunol. 2005 May 1;174(9):5805-13. doi: 10.4049/jimmunol.174.9.5805.
• [16] 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.
• [17] 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.
• [18] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [19] Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009 Nov;18(11):969-78. doi: 10.1111/j.1600-0625.2009.00884.x. Epub 2009 Apr 8.