Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8X4127)

• DOT Name: Glucosamine-6-phosphate isomerase 1 (GNPDA1)
• Synonyms: EC 3.5.99.6; Glucosamine-6-phosphate deaminase 1; GNPDA 1; GlcN6P deaminase 1; Oscillin
• Gene Name: GNPDA1
• UniProt ID: GNPI1_HUMAN
• PDB ID: 1NE7
• EC Number: 3.5.99.6
• Pfam ID: PF01182
• Sequence:
  MKLIILEHYSQASEWAAKYIRNRIIQFNPGPEKYFTLGLPTGSTPLGCYKKLIEYYKNGD
  LSFKYVKTFNMDEYVGLPRDHPESYHSFMWNNFFKHIDIHPENTHILDGNAVDLQAECDA
  FEEKIKAAGGIELFVGGIGPDGHIAFNEPGSSLVSRTRVKTLAMDTILANARFFDGELTK
  VPTMALTVGVGTVMDAREVMILITGAHKAFALYKAIEEGVNHMWTVSAFQQHPRTVFVCD
  EDATLELKVKTVKYFKGLMLVHNKLVDPLYSIKEKETEKSQSSKKPYSD
• Function: Catalyzes the reversible conversion of alpha-D-glucosamine 6-phosphate (GlcN-6P) into beta-D-fructose 6-phosphate (Fru-6P) and ammonium ion, a regulatory reaction step in de novo uridine diphosphate-N-acetyl-alpha-D-glucosamine (UDP-GlcNAc) biosynthesis via hexosamine pathway. Deamination is coupled to aldo-keto isomerization mediating the metabolic flux from UDP-GlcNAc toward Fru-6P. At high ammonium level can drive amination and isomerization of Fru-6P toward hexosamines and UDP-GlcNAc synthesis. Has a role in fine tuning the metabolic fluctuations of cytosolic UDP-GlcNAc and their effects on hyaluronan synthesis that occur during tissue remodeling. Seems to trigger calcium oscillations in mammalian eggs. These oscillations serve as the essential trigger for egg activation and early development of the embryo.
• KEGG Pathway:
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycolysis (R-HSA-70171)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[13]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glucosamine-6-phosphate isomerase 1 (GNPDA1).	[8]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [11] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [12] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [13] 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.
• [14] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.