Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLTDTR8)

• DOT Name: Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ)
• Synonyms: G(x) alpha chain; Gz-alpha
• Gene Name: GNAZ
• Related Disease:
  Bipolar disorder
  Congenital stationary night blindness
  Desmoid tumour
  Mantle cell lymphoma
  Stargardt disease
• UniProt ID: GNAZ_HUMAN
• PDB ID: 8DZS
• Pfam ID: PF00503
• Sequence:
  MGCRQSSEEKEAARRSRRIDRHLRSESQRQRREIKLLLLGTSNSGKSTIVKQMKIIHSGG
  FNLEACKEYKPLIIYNAIDSLTRIIRALAALRIDFHNPDRAYDAVQLFALTGPAESKGEI
  TPELLGVMRRLWADPGAQACFSRSSEYHLEDNAAYYLNDLERIAAADYIPTVEDILRSRD
  MTTGIVENKFTFKELTFKMVDVGGQRSERKKWIHCFEGVTAIIFCVELSGYDLKLYEDNQ
  TSRMAESLRLFDSICNNNWFINTSLILFLNKKDLLAEKIRRIPLTICFPEYKGQNTYEEA
  AVYIQRQFEDLNRNKETKEIYSHFTCATDTSNIQFVFDAVTDVIIQNNLKYIGLC
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.
• KEGG Pathway: Long-term depression (hsa04730)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[1]
Congenital stationary night blindness	DISX0CWK	Strong	Genetic Variation	[2]
Desmoid tumour	DISGX357	Strong	Altered Expression	[3]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[4]
Stargardt disease	DISPXOTO	Strong	Genetic Variation	[5]

13 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 Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[15]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[16]
Apicidin	DM83WVF	Investigative	Apicidin increases the expression of Guanine nucleotide-binding protein G(z) subunit alpha (GNAZ).	[17]

References

• [1] Analysis of GNAZ gene polymorphism in bipolar affective disorder.Am J Med Genet. 1999 Aug 20;88(4):324-8. doi: 10.1002/(sici)1096-8628(19990820)88:4<324::aid-ajmg7>3.0.co;2-m.
• [2] p.Gln200Glu, a putative constitutively active mutant of rod alpha-transducin (GNAT1) in autosomal dominant congenital stationary night blindness.Hum Mutat. 2007 Jul;28(7):741-2. doi: 10.1002/humu.9499.
• [3] A gene expression signature that distinguishes desmoid tumours from nodular fasciitis.J Pathol. 2006 Mar;208(4):543-53. doi: 10.1002/path.1915.
• [4] Expression of GNAZ, encoding the G(z) protein, predicts survival in mantle cell lymphoma.Br J Haematol. 2019 May;185(4):708-712. doi: 10.1111/bjh.15810. Epub 2019 Feb 20.
• [5] Mapping of the human cone transducin alpha-subunit (GNAT2) gene to 1p13 and negative mutation analysis in patients with Stargardt disease.Genomics. 1995 Jan 1;25(1):288-90. doi: 10.1016/0888-7543(95)80139-d.
• [6] 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.
• [7] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [17] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.