Details of Drug Off-Target (DOT)

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

• DOT Name: Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL)
• Synonyms: Adenylate cyclase-stimulating G alpha protein, olfactory type
• Gene Name: GNAL
• Related Disease:
  Bipolar disorder
  Bjornstad syndrome
  Cerebellar ataxia
  Dystonia 25
  Dystonia 5
  Focal dystonia
  Movement disorder
  Paroxysmal dystonia
  Schizophrenia
  Segmental dystonia
  Torsion dystonia 6
  Dystonia
  Parkinson disease
• UniProt ID: GNAL_HUMAN
• PDB ID: 8EL8; 8KGK; 8KH4
• Pfam ID: PF00503
• Sequence:
  MGCLGGNSKTTEDQGVDEKERREANKKIEKQLQKERLAYKATHRLLLLGAGESGKSTIVK
  QMRILHVNGFNPEEKKQKILDIRKNVKDAIVTIVSAMSTIIPPVPLANPENQFRSDYIKS
  IAPITDFEYSQEFFDHVKKLWDDEGVKACFERSNEYQLIDCAQYFLERIDSVSLVDYTPT
  DQDLLRCRVLTSGIFETRFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIYVAACSSY
  NMVIREDNNTNRLRESLDLFESIWNNRWLRTISIILFLNKQDMLAEKVLAGKSKIEDYFP
  EYANYTVPEDATPDAGEDPKVTRAKFFIRDLFLRISTATGDGKHYCYPHFTCAVDTENIR
  RVFNDCRDIIQRMHLKQYELL
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. G(olf) alpha mediates signal transduction within the olfactory neuroepithelium and the basal ganglia. May be involved in some aspect of visual transduction, and in mediating the effect of one or more hormones/neurotransmitters.
• Tissue Specificity: Detected in olfactory neuroepithelium, brain, testis, and to a lower extent in retina, lung alveoli, spleen. Trace amounts where seen in kidney, adrenal gland and liver. Found to be expressed in all the insulinomas examined.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Dopaminergic sy.pse (hsa04728)
  Olfactory transduction (hsa04740)
  Parkinson disease (hsa05012)
  Chagas disease (hsa05142)
  Amoebiasis (hsa05146)
• Reactome Pathway:
  Adenylate cyclase inhibitory pathway (R-HSA-170670)
  Olfactory Signaling Pathway (R-HSA-381753)
  Adenylate cyclase activating pathway (R-HSA-170660)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Altered Expression	[1]
Bjornstad syndrome	DISO267N	Strong	Genetic Variation	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Dystonia 25	DISIBRCT	Strong	Autosomal dominant	[4]
Dystonia 5	DISMPJ7S	Strong	Biomarker	[5]
Focal dystonia	DIS26D7O	Strong	Biomarker	[6]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[7]
Paroxysmal dystonia	DISV0MSQ	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[1]
Segmental dystonia	DISOACMU	Strong	Genetic Variation	[8]
Torsion dystonia 6	DIS2N5V6	Strong	Biomarker	[9]
Dystonia	DISJLFGW	Limited	Genetic Variation	[10]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[11]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Isoproterenol	DMK7MEY	Approved	Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL) increases the response to substance of Isoproterenol.	[24]
Azelaic Acid	DMHVL0J	Approved	Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL) increases the response to substance of Azelaic Acid.	[24]
geraniol	DMS3CBD	Investigative	Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL) increases the response to substance of geraniol.	[24]
Octanal	DMTN0OK	Investigative	Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL) increases the response to substance of Octanal.	[24]
Decanal	DMWZKLM	Investigative	Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL) increases the response to substance of Decanal.	[24]

2 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(olf) subunit alpha (GNAL).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[17]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL).	[23]

References

• [1] Alternative transcripts and evidence of imprinting of GNAL on 18p11.2.Mol Psychiatry. 2005 Nov;10(11):1017-25. doi: 10.1038/sj.mp.4001713.
• [2] Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls.Mov Disord. 2014 Jan;29(1):143-7. doi: 10.1002/mds.25715. Epub 2013 Oct 22.
• [3] Diagnosis and treatment of pediatric onset isolated dystonia.Eur J Paediatr Neurol. 2018 Mar;22(2):238-244. doi: 10.1016/j.ejpn.2018.01.006. Epub 2018 Jan 17.
• [4] 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.
• [5] New genetic insights highlight 'old' ideas on motor dysfunction in dystonia.Trends Neurosci. 2013 Dec;36(12):717-25. doi: 10.1016/j.tins.2013.09.003. Epub 2013 Oct 18.
• [6] Mutations in GNAL cause primary torsion dystonia. Nat Genet. 2013 Jan;45(1):88-92. doi: 10.1038/ng.2496. Epub 2012 Dec 9.
• [7] Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol.Exp Neurol. 2019 Aug;318:61-70. doi: 10.1016/j.expneurol.2019.04.014. Epub 2019 Apr 26.
• [8] Role of G(olf) in familial and sporadic adult-onset primary dystonia.Hum Mol Genet. 2013 Jun 15;22(12):2510-9. doi: 10.1093/hmg/ddt102. Epub 2013 Feb 27.
• [9] Inherited isolated dystonia: clinical genetics and gene function.Neurotherapeutics. 2014 Oct;11(4):807-16. doi: 10.1007/s13311-014-0297-7.
• [10] Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia.J Neurosci. 2019 Sep 4;39(36):7195-7205. doi: 10.1523/JNEUROSCI.0407-19.2019. Epub 2019 Jul 18.
• [11] Mutations in GNAL: a novel cause of craniocervical dystonia.JAMA Neurol. 2014 Apr;71(4):490-4. doi: 10.1001/jamaneurol.2013.4677.
• [12] 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.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] 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.
• [17] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [18] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] 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.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] 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.
• [24] Identification of specific ligands for orphan olfactory receptors. G protein-dependent agonism and antagonism of odorants. J Biol Chem. 2005 Mar 25;280(12):11807-15. doi: 10.1074/jbc.M411508200. Epub 2004 Dec 14.