Details of Drug Off-Target (DOT)

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

• DOT Name: GDP-fucose protein O-fucosyltransferase 1 (POFUT1)
• Synonyms: EC 2.4.1.221; Peptide-O-fucosyltransferase 1; O-FucT-1
• Gene Name: POFUT1
• Related Disease:
  Hypopigmentation of the skin
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Chronic obstructive pulmonary disease
  Congestive heart failure
  Dowling-Degos disease 2
  Ductal breast carcinoma in situ
  Hepatocellular carcinoma
  Invasive ductal breast carcinoma
  Myocardial infarction
  Neoplasm
  Schizophrenia
  Skin disease
  Isolated congenital microcephaly
  Dowling-Degos disease
  Colorectal adenoma
  Colorectal carcinoma
  Myeloproliferative neoplasm
• UniProt ID: OFUT1_HUMAN
• PDB ID: 5UX6; 5UXH
• EC Number: 2.4.1.221
• Pfam ID: PF10250
• Sequence:
  MGAAAWARPLSVSFLLLLLPLPGMPAGSWDPAGYLLYCPCMGRFGNQADHFLGSLAFAKL
  LNRTLAVPPWIEYQHHKPPFTNLHVSYQKYFKLEPLQAYHRVISLEDFMEKLAPTHWPPE
  KRVAYCFEVAAQRSPDKKTCPMKEGNPFGPFWDQFHVSFNKSELFTGISFSASYREQWSQ
  RFSPKEHPVLALPGAPAQFPVLEEHRPLQKYMVWSDEMVKTGEAQIHAHLVRPYVGIHLR
  IGSDWKNACAMLKDGTAGSHFMASPQCVGYSRSTAAPLTMTMCLPDLKEIQRAVKLWVRS
  LDAQSVYVATDSESYVPELQQLFKGKVKVVSLKPEVAQVDLYILGQADHFIGNCVSSFTA
  FVKRERDLQGRPSSFFGMDRPPKLRDEF
• Function: Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs).
• Tissue Specificity: Highly expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Other types of O-glycan biosynthesis (hsa00514)
• Reactome Pathway: Pre-NOTCH Processing in the Endoplasmic Reticulum (R-HSA-1912399)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypopigmentation of the skin	DIS39YKC	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Cardiac failure	DISDC067	Strong	Altered Expression	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[5]
Dowling-Degos disease 2	DISSK0FP	Strong	Autosomal dominant	[1]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[4]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
Skin disease	DISDW8R6	Strong	Genetic Variation	[9]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[10]
Dowling-Degos disease	DISGTTEP	Supportive	Autosomal dominant	[1]
Colorectal adenoma	DISTSVHM	Limited	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[7]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[16]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[17]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[20]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of GDP-fucose protein O-fucosyltransferase 1 (POFUT1).	[21]

References

• [1] Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet. 2013 Jun 6;92(6):895-903. doi: 10.1016/j.ajhg.2013.04.022. Epub 2013 May 16.
• [2] An integromic signature for lung cancer early detection.Oncotarget. 2018 May 15;9(37):24684-24692. doi: 10.18632/oncotarget.25227. eCollection 2018 May 15.
• [3] Caveolin-1 promotes invasion and metastasis by upregulating Pofut1 expression in mouse hepatocellular carcinoma.Cell Death Dis. 2019 Jun 17;10(7):477. doi: 10.1038/s41419-019-1703-1.
• [4] Overexpression of Pofut1 and activated Notch1 may be associated with poor prognosis in breast cancer.Biochem Biophys Res Commun. 2017 Sep 9;491(1):104-111. doi: 10.1016/j.bbrc.2017.07.053. Epub 2017 Jul 11.
• [5] Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1.Nat Commun. 2017 Sep 18;8(1):578. doi: 10.1038/s41467-017-00654-w.
• [6] Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.Nat Genet. 2017 Mar;49(3):426-432. doi: 10.1038/ng.3752. Epub 2017 Feb 6.
• [7] Weighted gene coexpression analysis indicates that PLAGL2 and POFUT1 are related to the differential features of proximal and distal colorectal cancer.Oncol Rep. 2019 Dec;42(6):2473-2485. doi: 10.3892/or.2019.7368. Epub 2019 Oct 14.
• [8] Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia.Schizophr Res. 2017 Apr;182:66-73. doi: 10.1016/j.schres.2016.10.024. Epub 2016 Oct 20.
• [9] Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions.Am J Med Genet A. 2019 Dec;179(12):2469-2473. doi: 10.1002/ajmg.a.61362. Epub 2019 Sep 30.
• [10] Variant in human POFUT1 reduces enzymatic activity and likely causes a recessive microcephaly, global developmental delay with cardiac and vascular features.Glycobiology. 2018 May 1;28(5):276-283. doi: 10.1093/glycob/cwy014.
• [11] Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression.Int J Cancer. 2020 Apr 1;146(7):1979-1992. doi: 10.1002/ijc.32627. Epub 2019 Aug 30.
• [12] Downregulating Notch counteracts Kras(G12D)-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm.Leukemia. 2019 Mar;33(3):671-685. doi: 10.1038/s41375-018-0248-0. Epub 2018 Sep 11.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [18] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [19] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [20] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [21] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.