Details of Drug Off-Target (DOT)

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

• DOT Name: 14-3-3 protein gamma
• Synonyms: Protein kinase C inhibitor protein 1; KCIP-1
• Gene Name: YWHAG
• Related Disease:
  Developmental and epileptic encephalopathy, 56
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: 1433G_HUMAN
• PDB ID: 2B05; 3UZD; 4E2E; 4J6S; 4O46; 5D3E; 6A5S; 6BYJ; 6BYL; 6BZD; 6FEL; 6GKF; 6GKG; 6S9K; 6SAD; 6Y4K; 6Y6B; 6ZBT; 6ZC9; 7A6R; 7A6Y
• Pfam ID: PF00244
• Sequence:
  MVDREQLVQKARLAEQAERYDDMAAAMKNVTELNEPLSNEERNLLSVAYKNVVGARRSSW
  RVISSIEQKTSADGNEKKIEMVRAYREKIEKELEAVCQDVLSLLDNYLIKNCSETQYESK
  VFYLKMKGDYYRYLAEVATGEKRATVVESSEKAYSEAHEISKEHMQPTHPIRLGLALNYS
  VFYYEIQNAPEQACHLAKTAFDDAIAELDTLNEDSYKDSTLIMQLLRDNLTLWTSDQQDD
  DGGEGNN
• Function: Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Promotes inactivation of WDR24 component of the GATOR2 complex by binding to phosphorylated WDR24.
• Tissue Specificity: Highly expressed in brain, skeletal muscle, and heart.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  PI3K-Akt sig.ling pathway (hsa04151)
  Hippo sig.ling pathway (hsa04390)
  Hepatitis C (hsa05160)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  RHO GTPases activate PKNs (R-HSA-5625740)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Chk1/Chk2(Cds1) mediated inactivation of Cyclin B (R-HSA-75035)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of localization of FOXO transcription factors (R-HSA-9614399)
  SARS-CoV-1 targets host intracellular signalling and regulatory pathways (R-HSA-9735871)
  SARS-CoV-2 targets host intracellular signalling and regulatory pathways (R-HSA-9755779)
  Activation of BAD and translocation to mitochondria (R-HSA-111447)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 56	DISYC23O	Definitive	Autosomal dominant	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]

11 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 14-3-3 protein gamma.	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 14-3-3 protein gamma.	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 14-3-3 protein gamma.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 14-3-3 protein gamma.	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 14-3-3 protein gamma.	[7]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of 14-3-3 protein gamma.	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 14-3-3 protein gamma.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of 14-3-3 protein gamma.	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of 14-3-3 protein gamma.	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 14-3-3 protein gamma.	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of 14-3-3 protein gamma.	[13]

1 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 14-3-3 protein gamma.	[6]

References

• [1] De Novo Mutations in YWHAG Cause Early-Onset Epilepsy. Am J Hum Genet. 2017 Aug 3;101(2):300-310. doi: 10.1016/j.ajhg.2017.07.004.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [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] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [8] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [9] Comparative mechanisms of PAH toxicity by benzo[a]pyrene and dibenzo[def,p]chrysene in primary human bronchial epithelial cells cultured at air-liquid interface. Toxicol Appl Pharmacol. 2019 Sep 15;379:114644.
• [10] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.