Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOYH4L9)

• DOT Name: Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1)
• Synonyms: EC 2.3.1.4; Phosphoglucosamine acetylase; Phosphoglucosamine transacetylase
• Gene Name: GNPNAT1
• Related Disease:
  Non-insulin dependent diabetes
  Lung adenocarcinoma
  Osteochondrodysplasia
  Type-1/2 diabetes
• UniProt ID: GNA1_HUMAN
• PDB ID: 2HUZ; 2O28; 3CXP; 3CXQ; 3CXS
• EC Number: 2.3.1.4
• Pfam ID: PF00583
• Sequence:
  MKPDETPMFDPSLLKEVDWSQNTATFSPAISPTHPGEGLVLRPLCTADLNRGFFKVLGQL
  TETGVVSPEQFMKSFEHMKKSGDYYVTVVEDVTLGQIVATATLIIEHKFIHSCAKRGRVE
  DVVVSDECRGKQLGKLLLSTLTLLSKKLNCYKITLECLPQNVGFYKKFGYTVSEENYMCR
  RFLK
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Osteochondrodysplasia	DIS9SPWW	Limited	Autosomal recessive	[3]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[4]

1 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 N-acetyltransferase (GNPNAT1).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Glucosamine 6-phosphate N-acetyltransferase (GNPNAT1).	[12]

References

• [1] Nanoparticle abraxane possesses impaired proliferation in A549 cells due to the underexpression of glucosamine 6-phosphate N-acetyltransferase 1 (GNPNAT1/GNA1).Int J Nanomedicine. 2017 Mar 1;12:1685-1697. doi: 10.2147/IJN.S129976. eCollection 2017.
• [2] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [3] Novel form of rhizomelic skeletal dysplasia associated with a homozygous variant in GNPNAT1. J Med Genet. 2021 May;58(5):351-356. doi: 10.1136/jmedgenet-2020-106929. Epub 2020 Jun 26.
• [4] Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease.Mol Cell Proteomics. 2017 Mar;16(3):368-385. doi: 10.1074/mcp.M116.061903. Epub 2017 Jan 4.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.