Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY0VAVL)

• DOT Name: Cytokine-like nuclear factor N-PAC (GLYR1)
• Synonyms: NPAC; 3-hydroxyisobutyrate dehydrogenase-like protein; Glyoxylate reductase 1 homolog; Nuclear protein NP60; Nuclear protein of 60 kDa; Nucleosome-destabilizing factor; hNDF; Putative oxidoreductase GLYR1
• Gene Name: GLYR1
• Related Disease:
  Colorectal carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Advanced cancer
  Breast cancer
  Breast carcinoma
• UniProt ID: GLYR1_HUMAN
• PDB ID: 2UYY; 4GUR; 4GUS; 4GUT; 4GUU; 4HSU; 6R1U; 6R25
• Pfam ID: PF14833 ; PF03446 ; PF00855
• Sequence:
  MAAVSLRLGDLVWGKLGRYPPWPGKIVNPPKDLKKPRGKKCFFVKFFGTEDHAWIKVEQL
  KPYHAHKEEMIKINKGKRFQQAVDAVEEFLRRAKGKDQTSSHNSSDDKNRRNSSEERSRP
  NSGDEKRKLSLSEGKVKKNMGEGKKRVSSGSSERGSKSPLKRAQEQSPRKRGRPPKDEKD
  LTIPESSTVKGMMAGPMAAFKWQPTASEPVKDADPHFHHFLLSQTEKPAVCYQAITKKLK
  ICEEETGSTSIQAADSTAVNGSITPTDKKIGFLGLGLMGSGIVSNLLKMGHTVTVWNRTA
  EKCDLFIQEGARLGRTPAEVVSTCDITFACVSDPKAAKDLVLGPSGVLQGIRPGKCYVDM
  STVDADTVTELAQVIVSRGGRFLEAPVSGNQQLSNDGMLVILAAGDRGLYEDCSSCFQAM
  GKTSFFLGEVGNAAKMMLIVNMVQGSFMATIAEGLTLAQVTGQSQQTLLDILNQGQLASI
  FLDQKCQNILQGNFKPDFYLKYIQKDLRLAIALGDAVNHPTPMAAAANEVYKRAKALDQS
  DNDMSAVYRAYIH
• Function: Cytokine-like nuclear factor with chromatin gene reader activity involved in chromatin modification and regulation of gene expression. Acts as a nucleosome-destabilizing factor that is recruited to genes during transcriptional activation. Recognizes and binds histone H3 without a preference for specific epigenetic markers and also binds DNA. Interacts with KDM1B and promotes its histone demethylase activity by facilitating the capture of H3 tails, they form a multifunctional enzyme complex that modifies transcribed chromatin and facilitates Pol II transcription through nucleosomes. Stimulates the acetylation of 'Lys-56' of nucleosomal histone H3 (H3K56ac) by EP300. With GATA4, co-binds a defined set of heart development genes and coregulates their expression during cardiomyocyte differentiation. Regulates p38 MAP kinase activity by mediating stress activation of MAPK14/p38alpha and specifically regulating MAPK14 signaling. Indirectly promotes phosphorylation of MAPK14 and activation of ATF2. The phosphorylation of MAPK14 requires upstream activity of MAP2K4 and MAP2K6.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cytokine-like nuclear factor N-PAC (GLYR1).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Cytokine-like nuclear factor N-PAC (GLYR1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cytokine-like nuclear factor N-PAC (GLYR1).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Cytokine-like nuclear factor N-PAC (GLYR1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytokine-like nuclear factor N-PAC (GLYR1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytokine-like nuclear factor N-PAC (GLYR1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cytokine-like nuclear factor N-PAC (GLYR1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytokine-like nuclear factor N-PAC (GLYR1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytokine-like nuclear factor N-PAC (GLYR1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytokine-like nuclear factor N-PAC (GLYR1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytokine-like nuclear factor N-PAC (GLYR1).	[15]

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 Cytokine-like nuclear factor N-PAC (GLYR1).	[9]

References

• [1] Candidate driver genes in microsatellite-unstable colorectal cancer.Int J Cancer. 2012 Apr 1;130(7):1558-66. doi: 10.1002/ijc.26167. Epub 2011 Aug 3.
• [2] Peripheral Insulin Extraction in Non-Diabetic Subjects and Type 2 Diabetes Mellitus Patients.Exp Clin Endocrinol Diabetes. 2020 Aug;128(8):520-527. doi: 10.1055/a-0808-4029. Epub 2018 Dec 17.
• [3] Cancer risk susceptibility loci in a Swedish population.Oncotarget. 2017 Nov 25;8(66):110300-110310. doi: 10.18632/oncotarget.22687. eCollection 2017 Dec 15.
• [4] NDF, a nucleosome-destabilizing factor that facilitates transcription through nucleosomes.Genes Dev. 2018 May 1;32(9-10):682-694. doi: 10.1101/gad.313973.118. Epub 2018 May 14.
• [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] 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.
• [7] 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.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] 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.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.