Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC1GPHA)

• DOT Name: Guanine nucleotide-binding protein subunit beta-4 (GNB4)
• Synonyms: Transducin beta chain 4
• Gene Name: GNB4
• Related Disease:
  Atrial fibrillation
  Bladder cancer
  Charcot-Marie-Tooth disease dominant intermediate F
  Colorectal carcinoma
  Crohn disease
  Ulcerative colitis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Charcot marie tooth disease
  Familial atrial fibrillation
  Colorectal neoplasm
• UniProt ID: GBB4_HUMAN
• Pfam ID: PF00400
• Sequence:
  MSELEQLRQEAEQLRNQIQDARKACNDATLVQITSNMDSVGRIQMRTRRTLRGHLAKIYA
  MHWGYDSRLLVSASQDGKLIIWDSYTTNKMHAIPLRSSWVMTCAYAPSGNYVACGGLDNI
  CSIYNLKTREGNVRVSRELPGHTGYLSCCRFLDDSQIVTSSGDTTCALWDIETAQQTTTF
  TGHSGDVMSLSLSPDMRTFVSGACDASSKLWDIRDGMCRQSFTGHVSDINAVSFFPNGYA
  FATGSDDATCRLFDLRADQELLLYSHDNIICGITSVAFSKSGRLLLAGYDDFNCNVWDTL
  KGDRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLRIWN
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
• Tissue Specificity: Strongly expressed in lung and placenta, whereas it is weakly expressed in brain and heart. Abundantly expressed in the axons and Schwann cells of peripheral nerves.
• 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:
  Glucagon signaling in metabolic regulation (R-HSA-163359)
  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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[2]
Charcot-Marie-Tooth disease dominant intermediate F	DISUUDF2	Strong	Autosomal dominant	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[4]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[4]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[2]
Charcot marie tooth disease	DIS3BT2L	Moderate	Autosomal dominant	[5]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[17]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Guanine nucleotide-binding protein subunit beta-4 (GNB4).	[16]

References

• [1] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [2] Association of GNB4 intron-1 haplotypes with survival in patients with UICC stage III and IV colorectal carcinoma.Anticancer Res. 2009 Apr;29(4):1271-4.
• [3] Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. Am J Hum Genet. 2013 Mar 7;92(3):422-30. doi: 10.1016/j.ajhg.2013.01.014. Epub 2013 Feb 21.
• [4] Identification of differentially expressed genes, associated functional terms pathways, and candidate diagnostic biomarkers in inflammatory bowel diseases by bioinformatics analysis.Exp Ther Med. 2019 Jul;18(1):278-288. doi: 10.3892/etm.2019.7541. Epub 2019 May 3.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.PLoS Genet. 2007 Sep;3(9):1709-23. doi: 10.1371/journal.pgen.0030157. Epub 2007 Jul 31.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] 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.
• [14] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.
• [18] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.