Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR4H8SJ)

• DOT Name: N-acetyl-D-glucosamine kinase (NAGK)
• Synonyms: N-acetylglucosamine kinase; EC 2.7.1.59; GlcNAc kinase; Muramyl dipeptide kinase; EC 2.7.1.-; N-acetyl-D-mannosamine kinase; EC 2.7.1.60
• Gene Name: NAGK
• Related Disease:
  Prostate cancer
  Prostate neoplasm
• UniProt ID: NAGK_HUMAN
• PDB ID: 2CH5; 2CH6
• EC Number: 2.7.1.-; 2.7.1.59; 2.7.1.60
• Pfam ID: PF01869
• Sequence:
  MAAIYGGVEGGGTRSEVLLVSEDGKILAEADGLSTNHWLIGTDKCVERINEMVNRAKRKA
  GVDPLVPLRSLGLSLSGGDQEDAGRILIEELRDRFPYLSESYLITTDAAGSIATATPDGG
  VVLISGTGSNCRLINPDGSESGCGGWGHMMGDEGSAYWIAHQAVKIVFDSIDNLEAAPHD
  IGYVKQAMFHYFQVPDRLGILTHLYRDFDKCRFAGFCRKIAEGAQQGDPLSRYIFRKAGE
  MLGRHIVAVLPEIDPVLFQGKIGLPILCVGSVWKSWELLKEGFLLALTQGREIQAQNFFS
  SFTLMKLRHSSALGGASLGARHIGHLLPMDYSANAIAFYSYTFS
• Function: Converts endogenous N-acetylglucosamine (GlcNAc), a major component of complex carbohydrates, from lysosomal degradation or nutritional sources into GlcNAc 6-phosphate. Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway: although human is not able to catalyze formation of Neu5Gc due to the inactive CMAHP enzyme, Neu5Gc is present in food and must be degraded. Also has N-acetylmannosamine (ManNAc) kinase activity. Also involved in innate immunity by promoting detection of bacterial peptidoglycan by NOD2: acts by catalyzing phosphorylation of muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, to generate 6-O-phospho-muramyl dipeptide, which acts as a direct ligand for NOD2.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of nucleotide sugars (hsa01250)
• Reactome Pathway: Synthesis of UDP-N-acetyl-glucosamine (R-HSA-446210)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of N-acetyl-D-glucosamine kinase (NAGK).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of N-acetyl-D-glucosamine kinase (NAGK).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of N-acetyl-D-glucosamine kinase (NAGK).	[15]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] 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.
• [10] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.