Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3KETR8)

• DOT Name: Glucosamine-6-phosphate isomerase 2 (GNPDA2)
• Synonyms: EC 3.5.99.6; Glucosamine-6-phosphate deaminase 2; GNPDA 2; GlcN6P deaminase 2; Glucosamine-6-phosphate isomerase SB52
• Gene Name: GNPDA2
• UniProt ID: GNPI2_HUMAN
• EC Number: 3.5.99.6
• Pfam ID: PF01182
• Sequence:
  MRLVILDNYDLASEWAAKYICNRIIQFKPGQDRYFTLGLPTGSTPLGCYKKLIEYHKNGH
  LSFKYVKTFNMDEYVGLPRNHPESYHSYMWNNFFKHIDIDPNNAHILDGNAADLQAECDA
  FENKIKEAGGIDLFVGGIGPDGHIAFNEPGSSLVSRTRLKTLAMDTILANAKYFDGDLSK
  VPTMALTVGVGTVMDAREVMILITGAHKAFALYKAIEEGVNHMWTVSAFQQHPRTIFVCD
  EDATLELRVKTVKYFKGLMHVHNKLVDPLFSMKDGN
• 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.
• Tissue Specificity: Ubiquitous, with highest expression detected in testis, ovary, placenta, and heart.
• 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

5 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 Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the methylation of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[7]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glucosamine-6-phosphate isomerase 2 (GNPDA2).	[12]

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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] 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.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Epigenetic activation of O-linked -N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia. EBioMedicine. 2020 Apr;54:102678. doi: 10.1016/j.ebiom.2020.102678. Epub 2020 Apr 6.
• [9] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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 and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.