Details of Drug Off-Target (DOT)

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

• DOT Name: Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE)
• Synonyms: UDP-GlcNAc-2-epimerase/ManAc kinase
• Gene Name: GNE
• Related Disease:
  GNE myopathy
  Sialuria
  Macrothrombocytopenia, isolated
  Platelet-type bleeding disorder 19
• UniProt ID: GLCNE_HUMAN
• PDB ID: 2YHW; 2YHY; 2YI1; 3EO3; 4ZHT
• EC Number: 2.7.1.60; 3.2.1.183
• Pfam ID: PF02350 ; PF00480
• Sequence:
  MEKNGNNRKLRVCVATCNRADYSKLAPIMFGIKTEPEFFELDVVVLGSHLIDDYGNTYRM
  IEQDDFDINTRLHTIVRGEDEAAMVESVGLALVKLPDVLNRLKPDIMIVHGDRFDALALA
  TSAALMNIRILHIEGGEVSGTIDDSIRHAITKLAHYHVCCTRSAEQHLISMCEDHDRILL
  AGCPSYDKLLSAKNKDYMSIIRMWLGDDVKSKDYIVALQHPVTTDIKHSIKMFELTLDAL
  ISFNKRTLVLFPNIDAGSKEMVRVMRKKGIEHHPNFRAVKHVPFDQFIQLVAHAGCMIGN
  SSCGVREVGAFGTPVINLGTRQIGRETGENVLHVRDADTQDKILQALHLQFGKQYPCSKI
  YGDGNAVPRILKFLKSIDLQEPLQKKFCFPPVKENISQDIDHILETLSALAVDLGGTNLR
  VAIVSMKGEIVKKYTQFNPKTYEERINLILQMCVEAAAEAVKLNCRILGVGISTGGRVNP
  REGIVLHSTKLIQEWNSVDLRTPLSDTLHLPVWVDNDGNCAALAERKFGQGKGLENFVTL
  ITGTGIGGGIIHQHELIHGSSFCAAELGHLVVSLDGPDCSCGSHGCIEAYASGMALQREA
  KKLHDEDLLLVEGMSVPKDEAVGALHLIQAAKLGNAKAQSILRTAGTALGLGVVNILHTM
  NPSLVILSGVLASHYIHIVKDVIRQQALSSVQDVDVVVSDLVDPALLGAASMVLDYTTRR
  IY
• Function: Bifunctional enzyme that possesses both UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities, and serves as the initiator of the biosynthetic pathway leading to the production of N-acetylneuraminic acid (NeuAc), a critical precursor in the synthesis of sialic acids. By catalyzing this pivotal and rate-limiting step in sialic acid biosynthesis, this enzyme assumes a pivotal role in governing the regulation of cell surface sialylation. Sialic acids represent a category of negatively charged sugars that reside on the surface of cells as terminal components of glycoconjugates and mediate important functions in various cellular processes, including cell adhesion, signal transduction, and cellular recognition.
• Tissue Specificity: Highest expression in liver and placenta. Also found in heart, brain, lung, kidney, skeletal muscle and pancreas. Isoform 1 is expressed in heart, brain, kidney, liver, placenta, lung, spleen, pancreas, skeletal muscle and colon. Isoform 2 is expressed mainly in placenta, but also in brain, kidney, liver, lung, pancreas and colon. Isoform 3 is expressed at low level in kidney, liver, placenta and colon.
• KEGG Pathway:
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of nucleotide sugars (hsa01250)
• Reactome Pathway:
  Defective GNE causes sialuria, NK and IBM2 (R-HSA-4085011)
  Sialic acid metabolism (R-HSA-4085001)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
GNE myopathy	DIS73X4W	Definitive	Autosomal recessive	[1]
Sialuria	DISK9T5J	Strong	Autosomal dominant	[2]
Macrothrombocytopenia, isolated	DISL5G2O	Moderate	Autosomal recessive	[1]
Platelet-type bleeding disorder 19	DISPVLDT	Supportive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) affects the response to substance of Methotrexate.	[21]

15 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 Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[19]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] GNE variants causing autosomal recessive macrothrombocytopenia without associated muscle wasting. Blood. 2018 Oct 25;132(17):1851-1854. doi: 10.1182/blood-2018-04-845545. Epub 2018 Aug 31.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [12] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [15] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [16] 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.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.