Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVFS16E)

• DOT Name: UDP-glucose 4-epimerase (GALE)
• Synonyms: EC 5.1.3.2; Galactowaldenase; UDP-N-acetylgalactosamine 4-epimerase; UDP-GalNAc 4-epimerase; UDP-N-acetylglucosamine 4-epimerase; UDP-GlcNAc 4-epimerase; EC 5.1.3.7; UDP-galactose 4-epimerase
• Gene Name: GALE
• Related Disease: Galactose epimerase deficiency
• UniProt ID: GALE_HUMAN
• PDB ID: 1EK5; 1EK6; 1HZJ; 1I3K; 1I3L; 1I3M; 1I3N
• EC Number: 5.1.3.2; 5.1.3.7
• Pfam ID: PF16363
• Sequence:
  MAEKVLVTGGAGYIGSHTVLELLEAGYLPVVIDNFHNAFRGGGSLPESLRRVQELTGRSV
  EFEEMDILDQGALQRLFKKYSFMAVIHFAGLKAVGESVQKPLDYYRVNLTGTIQLLEIMK
  AHGVKNLVFSSSATVYGNPQYLPLDEAHPTGGCTNPYGKSKFFIEEMIRDLCQADKTWNA
  VLLRYFNPTGAHASGCIGEDPQGIPNNLMPYVSQVAIGRREALNVFGNDYDTEDGTGVRD
  YIHVVDLAKGHIAALRKLKEQCGCRIYNLGTGTGYSVLQMVQAMEKASGKKIPYKVVARR
  EGDVAACYANPSLAQEELGWTAALGLDRMCEDLWRWQKQNPSGFGTQA
• Function: Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The reaction with UDP-Gal plays a critical role in the Leloir pathway of galactose catabolism in which galactose is converted to the glycolytic intermediate glucose 6-phosphate. It contributes to the catabolism of dietary galactose and enables the endogenous biosynthesis of both UDP-Gal and UDP-GalNAc when exogenous sources are limited. Both UDP-sugar interconversions are important in the synthesis of glycoproteins and glycolipids.
• KEGG Pathway:
  Galactose metabolism (hsa00052)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of nucleotide sugars (hsa01250)
• Reactome Pathway:
  Galactose catabolism (R-HSA-70370)
  Defective GALE causes EDG (R-HSA-5609977)
• BioCyc Pathway: MetaCyc:HS04117-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Galactose epimerase deficiency	DIS16BDZ	Definitive	Autosomal recessive	[1]

14 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 UDP-glucose 4-epimerase (GALE).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of UDP-glucose 4-epimerase (GALE).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of UDP-glucose 4-epimerase (GALE).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of UDP-glucose 4-epimerase (GALE).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of UDP-glucose 4-epimerase (GALE).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of UDP-glucose 4-epimerase (GALE).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of UDP-glucose 4-epimerase (GALE).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of UDP-glucose 4-epimerase (GALE).	[9]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of UDP-glucose 4-epimerase (GALE).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of UDP-glucose 4-epimerase (GALE).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of UDP-glucose 4-epimerase (GALE).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of UDP-glucose 4-epimerase (GALE).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of UDP-glucose 4-epimerase (GALE).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of UDP-glucose 4-epimerase (GALE).	[16]

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 decreases the methylation of UDP-glucose 4-epimerase (GALE).	[12]

4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
UDP-glucuronic acid	DMW16X2	Investigative	UDP-glucuronic acid affects the binding of UDP-glucose 4-epimerase (GALE).	[17]
UDP-glucose	DMLT4JA	Investigative	UDP-glucose affects the binding of UDP-glucose 4-epimerase (GALE).	[17]
Uridine diphosphate galactose	DMPA0BJ	Investigative	Uridine diphosphate galactose affects the binding of UDP-glucose 4-epimerase (GALE).	[17]
Uridine-Diphosphate-N-Acetylgalactosamine	DMXHO6J	Investigative	Uridine-Diphosphate-N-Acetylgalactosamine affects the binding of UDP-glucose 4-epimerase (GALE).	[17]

References

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• [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] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [10] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [17] Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. Chem Biol Interact. 2015 Jun 5;234:114-25.