Details of Drug Off-Target (DOT)

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

• DOT Name: 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9)
• Synonyms: EC 2.4.1.152; Fucosyltransferase 9; Fucosyltransferase IX; Fuc-TIX; FucT-IX; Galactoside 3-L-fucosyltransferase
• Gene Name: FUT9
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Neoplasm
  Lung carcinoma
  Malaria
  Colon adenocarcinoma
• UniProt ID: FUT9_HUMAN
• PDB ID: 8D0O; 8D0P; 8D0Q; 8D0R; 8D0S; 8D0U; 8D0W; 8D0X
• EC Number: 2.4.1.152
• Pfam ID: PF17039 ; PF00852
• Sequence:
  MTSTSKGILRPFLIVCIILGCFMACLLIYIKPTNSWIFSPMESASSVLKMKNFFSTKTDY
  FNETTILVWVWPFGQTFDLTSCQAMFNIQGCHLTTDRSLYNKSHAVLIHHRDISWDLTNL
  PQQARPPFQKWIWMNLESPTHTPQKSGIEHLFNLTLTYRRDSDIQVPYGFLTVSTNPFVF
  EVPSKEKLVCWVVSNWNPEHARVKYYNELSKSIEIHTYGQAFGEYVNDKNLIPTISTCKF
  YLSFENSIHKDYITEKLYNAFLAGSVPVVLGPSRENYENYIPADSFIHVEDYNSPSELAK
  YLKEVDKNNKLYLSYFNWRKDFTVNLPRFWESHACLACDHVKRHQEYKSVGNLEKWFWN
• Function: Catalyzes alpha(1->3) linkage of fucosyl moiety transferred from GDP-beta-L-fucose to N-acetyl glucosamine (GlcNAc) within type 2 lactosamine (LacNAc, beta-D-Gal-(1->4)-beta-D-GlcNAc-) glycan attached to glycolipids and N- or O-linked glycoproteins. Fucosylates distal type 2 LacNAc and its fucosylated (H-type 2 LacNAc) and sialylated (sialyl-type 2 LacNAc) derivatives to form Lewis x (Lex) (CD15) and Lewis y (Ley) antigenic epitopes involved in cell adhesion and differentiation. Generates Lex epitopes in the brain, presumably playing a role in the maintenance of neuronal stemness and neurite outgrowth in progenitor neural cells. Fucosylates the internal type 2 LacNAc unit of the polylactosamine chain to form VIM-2 antigen that serves as recognition epitope for SELE. Can also modify milk oligosaccharides, in particular type 2 tetrasaccharide LNnT.
• Tissue Specificity: Strongly expressed in forebrain and stomach, lower expression in spleen and peripheral blood leukocytes, and no expression in small intestine, colon, liver, lung, kidney, adrenal cortex or uterus . Highly expressed in granulocytes. Not expressed in monocytes .
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Glycosphingolipid biosynthesis - globo and isoglobo series (hsa00603)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Lewis blood group biosynthesis (R-HSA-9037629)
• BioCyc Pathway: MetaCyc:HS10520-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 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	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	moderate	Biomarker	[4]
Malaria	DISQ9Y50	Disputed	Genetic Variation	[5]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9).	[13]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase 9 (FUT9).	[12]

References

• [1] An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer.Mol Syst Biol. 2017 Dec 1;13(12):956. doi: 10.15252/msb.20177739.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] A variant in the gene FUT9 is associated with susceptibility to placental malaria infection.Hum Mol Genet. 2009 Aug 15;18(16):3136-44. doi: 10.1093/hmg/ddp240. Epub 2009 May 21.
• [6] 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.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [10] 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.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] 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.