Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4EDVGT)

• DOT Name: GDP-L-fucose synthase (GFUS)
• Synonyms: EC 1.1.1.271; GDP-4-keto-6-deoxy-D-mannose-3,5-epimerase-4-reductase; Protein FX; Red cell NADP(H)-binding protein; Short-chain dehydrogenase/reductase family 4E member 1
• Gene Name: GFUS
• UniProt ID: FCL_HUMAN
• PDB ID: 4B8W; 4B8Z; 4BKP; 4BL5; 4E5Y
• EC Number: 1.1.1.271
• Pfam ID: PF01370
• Sequence:
  MGEPQGSMRILVTGGSGLVGKAIQKVVADGAGLPGEDWVFVSSKDADLTDTAQTRALFEK
  VQPTHVIHLAAMVGGLFRNIKYNLDFWRKNVHMNDNVLHSAFEVGARKVVSCLSTCIFPD
  KTTYPIDETMIHNGPPHNSNFGYSYAKRMIDVQNRAYFQQYGCTFTAVIPTNVFGPHDNF
  NIEDGHVLPGLIHKVHLAKSSGSALTVWGTGNPRRQFIYSLDLAQLFIWVLREYNEVEPI
  ILSVGEEDEVSIKEAAEAVVEAMDFHGEVTFDTTKSDGQFKKTASNSKLRTYLPDFRFTP
  FKQAVKETCAWFTDNYEQARK
• Function: Catalyzes the two-step NADP-dependent conversion of GDP-4-dehydro-6-deoxy-D-mannose to GDP-fucose, involving an epimerase and a reductase reaction.
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of nucleotide sugars (hsa01250)
• Reactome Pathway: GDP-fucose biosynthesis (R-HSA-6787639)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	GDP-L-fucose synthase (GFUS) affects the response to substance of Acetaminophen.	[8]

2 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-L-fucose synthase (GFUS).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of GDP-L-fucose synthase (GFUS).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GDP-L-fucose synthase (GFUS).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GDP-L-fucose synthase (GFUS).	[4]
Marinol	DM70IK5	Approved	Marinol decreases the expression of GDP-L-fucose synthase (GFUS).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of GDP-L-fucose synthase (GFUS).	[6]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of GDP-L-fucose synthase (GFUS).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of GDP-L-fucose synthase (GFUS).	[6]

References

• [1] 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.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] 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.
• [5] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [8] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.