Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK2SNJA)

• DOT Name: Guanine nucleotide-binding protein G(t) subunit alpha-1 (GNAT1)
• Synonyms: Transducin alpha-1 chain
• Gene Name: GNAT1
• Related Disease:
  Congenital stationary night blindness autosomal dominant 3
  Colorectal carcinoma
  Diabetic retinopathy
  Retinitis pigmentosa
  Type-1/2 diabetes
  Neoplasm
  Congenital stationary night blindness
  Congenital stationary night blindness 1G
  Gastric cancer
  Late-onset retinal degeneration
  Stomach cancer
• UniProt ID: GNAT1_HUMAN
• PDB ID: 3RBQ
• Pfam ID: PF00503
• Sequence:
  MGAGASAEEKHSRELEKKLKEDAEKDARTVKLLLLGAGESGKSTIVKQMKIIHQDGYSLE
  ECLEFIAIIYGNTLQSILAIVRAMTTLNIQYGDSARQDDARKLMHMADTIEEGTMPKEMS
  DIIQRLWKDSGIQACFERASEYQLNDSAGYYLSDLERLVTPGYVPTEQDVLRSRVKTTGI
  IETQFSFKDLNFRMFDVGGQRSERKKWIHCFEGVTCIIFIAALSAYDMVLVEDDEVNRMH
  ESLHLFNSICNHRYFATTSIVLFLNKKDVFFEKIKKAHLSICFPDYDGPNTYEDAGNYIK
  VQFLELNMRRDVKEIYSHMTCATDTQNVKFVFDAVTDIIIKENLKDCGLF
• Function: Functions as a signal transducer for the rod photoreceptor RHO. Required for normal RHO-mediated light perception by the retina. Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs), such as the photoreceptor RHO. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Activated RHO promotes GDP release and GTP binding. Signaling is mediated via downstream effector proteins, such as cGMP-phosphodiesterase.
• Tissue Specificity: Rod photoreceptor cells . Predominantly expressed in the retina followed by the ciliary body, iris and retinal pigment epithelium .
• KEGG Pathway: Phototransduction (hsa04744)
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  G alpha (i) signalling events (R-HSA-418594)
  Activation of the phototransduction cascade (R-HSA-2485179)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital stationary night blindness autosomal dominant 3	DIS5GHJ9	Definitive	Autosomal dominant	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[3]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[5]
Congenital stationary night blindness	DISX0CWK	Supportive	Autosomal dominant	[6]
Congenital stationary night blindness 1G	DISR8TAE	Limited	Autosomal recessive	[7]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[5]
Late-onset retinal degeneration	DIST9GP4	Limited	Biomarker	[8]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[5]

1 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 Guanine nucleotide-binding protein G(t) subunit alpha-1 (GNAT1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Guanine nucleotide-binding protein G(t) subunit alpha-1 (GNAT1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guanine nucleotide-binding protein G(t) subunit alpha-1 (GNAT1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Guanine nucleotide-binding protein G(t) subunit alpha-1 (GNAT1).	[12]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Guanine nucleotide-binding protein G(t) subunit alpha-1 (GNAT1).	[13]

References

• [1] A Novel Heterozygous Missense Mutation in GNAT1 Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness. Biomed Res Int. 2018 Apr 23;2018:7694801. doi: 10.1155/2018/7694801. eCollection 2018.
• [2] A novel long non-coding RNA lnc-GNAT1-1 is low expressed in colorectal cancer and acts as a tumor suppressor through regulating RKIP-NF-B-Snail circuit.J Exp Clin Cancer Res. 2016 Dec 3;35(1):187. doi: 10.1186/s13046-016-0467-z.
• [3] Transducin1, Phototransduction and the Development of Early Diabetic Retinopathy.Invest Ophthalmol Vis Sci. 2019 Apr 1;60(5):1538-1546. doi: 10.1167/iovs.18-26433.
• [4] Autophagy in Xenopus laevis rod photoreceptors is independently regulated by phototransduction and misfolded RHO(P23H).Autophagy. 2019 Nov;15(11):1970-1989. doi: 10.1080/15548627.2019.1596487. Epub 2019 Apr 12.
• [5] Long noncoding RNA lncGNAT1? inhibits gastric cancer cell proliferation and invasion through the Wnt/catenin pathway in Helicobacterpylori infection.Mol Med Rep. 2018 Oct;18(4):4009-4015. doi: 10.3892/mmr.2018.9405. Epub 2018 Aug 20.
• [6] Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of congenital stationary night blindness. Nat Genet. 1996 Jul;13(3):358-60. doi: 10.1038/ng0796-358.
• [7] GNAT1 associated with autosomal recessive congenital stationary night blindness. Invest Ophthalmol Vis Sci. 2012 Mar 13;53(3):1353-61. doi: 10.1167/iovs.11-8026. Print 2012 Mar.
• [8] A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration.Br J Ophthalmol. 2016 Apr;100(4):495-500. doi: 10.1136/bjophthalmol-2015-306939. Epub 2015 Oct 15.
• [9] 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.
• [10] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.