Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1MNJFZ)

• DOT Name: GDP-fucose protein O-fucosyltransferase 2 (POFUT2)
• Synonyms: EC 2.4.1.221; Peptide-O-fucosyltransferase 2; O-FucT-2
• Gene Name: POFUT2
• Related Disease:
  Malaria
  Congenital disorder of glycosylation
  Peters plus syndrome
  Popliteal pterygium syndrome
  Schizophrenia
• UniProt ID: OFUT2_HUMAN
• PDB ID: 4AP5; 4AP6
• EC Number: 2.4.1.221
• Pfam ID: PF10250
• Sequence:
  MATLSFVFLLLGAVSWPPASASGQEFWPGQSAADILSGAASRRRYLLYDVNPPEGFNLRR
  DVYIRIASLLKTLLKTEEWVLVLPPWGRLYHWQSPDIHQVRIPWSEFFDLPSLNKNIPVI
  EYEQFIAESGGPFIDQVYVLQSYAEGWKEGTWEEKVDERPCIDQLLYSQDKHEYYRGWFW
  GYEETRGLNVSCLSVQGSASIVAPLLLRNTSARSVMLDRAENLLHDHYGGKEYWDTRRSM
  VFARHLREVGDEFRSRHLNSTDDADRIPFQEDWMKMKVKLGSALGGPYLGVHLRRKDFIW
  GHRQDVPSLEGAVRKIRSLMKTHRLDKVFVATDAVRKEYEELKKLLPEMVRFEPTWEELE
  LYKDGGVAIIDQWICAHARFFIGTSVSTFSFRIHEEREILGLDPKTTYNRFCGDQEKACE
  QPTHWKITY
• Function: Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue in the consensus sequence C1-X-X-S/T-C2 of thrombospondin type I repeats (TSRs) where C1 and C2 are the first and second cysteines of the repeat, respectively. O-fucosylates members of several protein families including the ADAMTS, the thrombospondin (TSP) and spondin families (Probable). Required for the proper secretion of ADAMTS family members such as ADAMTSL1 and ADAMTS13. The O-fucosylation of TSRs is also required for restricting epithelial to mesenchymal transition (EMT), maintaining the correct patterning of mesoderm and localization of the definite endoderm.
• Tissue Specificity: Isoform A is expressed in fetal liver and peripheral blood lymphocytes. Isoform B is expressed in spleen, lung, testis, bone marrow, thymus, pancreas, prostate, fetal brain, fetal liver and fetal kidney. Isoform C is expressed in brain, heart, spleen, liver, lung, stomach, testis, placenta, skin, thymus, pancreas, mammary gland, prostate, fetal brain, fetal liver and fetal heart.
• KEGG Pathway: Other types of O-glycan biosynthesis (hsa00514)
• Reactome Pathway: O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Biomarker	[1]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[2]
Peters plus syndrome	DISIUM7O	Strong	Genetic Variation	[2]
Popliteal pterygium syndrome	DISRS4H8	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[4]

4 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 GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of GDP-fucose protein O-fucosyltransferase 2 (POFUT2).	[12]

References

• [1] Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts.Nat Commun. 2017 Sep 15;8(1):561. doi: 10.1038/s41467-017-00571-y.
• [2] Analyzing the Effects of O-Fucosylation on Secretion of ADAMTS Proteins Using Cell-Based Assays.Methods Mol Biol. 2020;2043:25-43. doi: 10.1007/978-1-4939-9698-8_3.
• [3] Peters plus syndrome mutations disrupt a noncanonical ER quality-control mechanism.Curr Biol. 2015 Feb 2;25(3):286-295. doi: 10.1016/j.cub.2014.11.049. Epub 2014 Dec 24.
• [4] 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.
• [5] 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.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.