Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ZSAXH)

• DOT Name: Guanine nucleotide-binding protein subunit beta-5 (GNB5)
• Synonyms: Gbeta5; Transducin beta chain 5
• Gene Name: GNB5
• Related Disease:
  Colorectal carcinoma
  Colorectal neoplasm
  Autism
  Colon cancer
  Colon carcinoma
  Disorder of orbital region
  Epilepsy
  Gnb5-related intellectual disability-cardiac arrhythmia syndrome
  Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia
  Intellectual disability
  Neurodevelopmental disorder
  Schizophrenia
• UniProt ID: GNB5_HUMAN
• PDB ID: 7EWP; 7EWR; 8SG8; 8SG9; 8SGC; 8SGL; 8SH9; 8SHA; 8SHD; 8SHE; 8SHF; 8SHG; 8SHL; 8SHN; 8SHO; 8SHP; 8SHQ; 8SHT
• Pfam ID: PF00400
• Sequence:
  MCDQTFLVNVFGSCDKCFKQRALRPVFKKSQQLSYCSTCAEIMATEGLHENETLASLKSE
  AESLKGKLEEERAKLHDVELHQVAERVEALGQFVMKTRRTLKGHGNKVLCMDWCKDKRRI
  VSSSQDGKVIVWDSFTTNKEHAVTMPCTWVMACAYAPSGCAIACGGLDNKCSVYPLTFDK
  NENMAAKKKSVAMHTNYLSACSFTNSDMQILTASGDGTCALWDVESGQLLQSFHGHGADV
  LCLDLAPSETGNTFVSGGCDKKAMVWDMRSGQCVQAFETHESDINSVRYYPSGDAFASGS
  DDATCRLYDLRADREVAIYSKESIIFGASSVDFSLSGRLLFAGYNDYTINVWDVLKGSRV
  SILFGHENRVSTLRVSPDGTAFCSGSWDHTLRVWA
• Function: Enhances GTPase-activating protein (GAP) activity of regulator of G protein signaling (RGS) proteins, such as RGS7 and RGS9, hence involved in the termination of the signaling initiated by the G protein coupled receptors (GPCRs) by accelerating the GTP hydrolysis on the G-alpha subunits, thereby promoting their inactivation. Increases RGS7 GTPase-activating protein (GAP) activity, thereby regulating mood and cognition. Increases RGS9 GTPase-activating protein (GAP) activity, hence contributes to the deactivation of G protein signaling initiated by D(2) dopamine receptors. May play an important role in neuronal signaling, including in the parasympathetic, but not sympathetic, control of heart rate.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apelin sig.ling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Relaxin sig.ling pathway (hsa04926)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G-protein activation (R-HSA-202040)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  ADP signalling through P2Y purinoceptor 12 (R-HSA-392170)
  G beta (R-HSA-392451)
  Prostacyclin signalling through prostacyclin receptor (R-HSA-392851)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  G beta (R-HSA-418217)
  G alpha (s) signalling events (R-HSA-418555)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Glucagon-type ligand receptors (R-HSA-420092)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  G beta (R-HSA-8964315)
  G beta (R-HSA-8964616)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Definitive	Biomarker	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Disorder of orbital region	DISH0ECJ	Strong	Genetic Variation	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Gnb5-related intellectual disability-cardiac arrhythmia syndrome	DISP2K58	Strong	Autosomal recessive	[6]
Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia	DISS7KVL	Strong	Autosomal recessive	[7]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[8]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[9]
Schizophrenia	DISSRV2N	No Known	Unknown	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[20]
N-(3-METHYLBUT-2-EN-1-YL)-9H-PURIN-6-AMINE	DM2D4KY	Investigative	N-(3-METHYLBUT-2-EN-1-YL)-9H-PURIN-6-AMINE decreases the expression of Guanine nucleotide-binding protein subunit beta-5 (GNB5).	[21]

References

• [1] Highly Expressed Genes in Rapidly Proliferating Tumor Cells as New Targets for Colorectal Cancer Treatment.Clin Cancer Res. 2015 Aug 15;21(16):3695-704. doi: 10.1158/1078-0432.CCR-14-2457. Epub 2015 May 5.
• [2] A NGS-Targeted Autism/ID Panel Reveals Compound Heterozygous GNB5 Variants in a Novel Patient.Front Genet. 2018 Dec 12;9:626. doi: 10.3389/fgene.2018.00626. eCollection 2018.
• [3] Comprehensive genomic analyses of a metastatic colon cancer to the lung by whole exome sequencing and gene expression analysis.Int J Oncol. 2014 Jan;44(1):211-21. doi: 10.3892/ijo.2013.2150. Epub 2013 Oct 25.
• [4] GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. Am J Hum Genet. 2016 Sep 1;99(3):704-710. doi: 10.1016/j.ajhg.2016.06.025. Epub 2016 Aug 11.
• [5] Generation of the induced human pluripotent stem cell lines CSSi009-A from a patient with a GNB5 pathogenic variant, and CSSi010-A from a CRISPR/Cas9 engineered GNB5 knock-out human cell line.Stem Cell Res. 2019 Oct;40:101547. doi: 10.1016/j.scr.2019.101547. Epub 2019 Aug 22.
• [6] G5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems. Psychopharmacology (Berl). 2012 Feb;219(3):823-34. doi: 10.1007/s00213-011-2409-y. Epub 2011 Jul 16.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.Clin Genet. 2018 Jun;93(6):1254-1256. doi: 10.1111/cge.13194. Epub 2018 Jan 25.
• [9] The epileptology of GNB5 encephalopathy.Epilepsia. 2019 Nov;60(11):e121-e127. doi: 10.1111/epi.16372. Epub 2019 Oct 20.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [16] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] 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.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Immediate up-regulation of the calcium-binding protein S100P and its involvement in the cytokinin-induced differentiation of human myeloid leukemia cells. Biochim Biophys Acta. 2005 Sep 10;1745(2):156-65.