Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEPUP1U)

• DOT Name: Guanine nucleotide-binding protein G(T) subunit gamma-T1 (GNGT1)
• Synonyms: Transducin gamma chain
• Gene Name: GNGT1
• Related Disease:
  Breast carcinoma
  Epithelial ovarian cancer
  Rectal adenocarcinoma
• UniProt ID: GBG1_HUMAN
• PDB ID: 7L0P; 7L0Q; 7L0R; 7L0S
• Pfam ID: PF00631
• Sequence:
  MPVINIEDLTEKDKLKMEVDQLKKEVTLERMLVSKCCEEVRDYVEERSGEDPLVKGIPED
  KNPFKELKGGCVIS
• 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: Retinal rod outer segment.
• 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)
  Phototransduction (hsa04744)
  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)
  Activation of the phototransduction cascade (R-HSA-2485179)
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Rectal adenocarcinoma	DIS8R9VO	Strong	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Guanine nucleotide-binding protein G(T) subunit gamma-T1 (GNGT1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Guanine nucleotide-binding protein G(T) subunit gamma-T1 (GNGT1).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Guanine nucleotide-binding protein G(T) subunit gamma-T1 (GNGT1).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Guanine nucleotide-binding protein G(T) subunit gamma-T1 (GNGT1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Guanine nucleotide-binding protein G(T) subunit gamma-T1 (GNGT1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Guanine nucleotide-binding protein G(T) subunit gamma-T1 (GNGT1).	[6]

References

• [1] Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci.Pharmacogenet Genomics. 2018 Feb;28(2):49-55. doi: 10.1097/FPC.0000000000000318.
• [2] Evaluation of core serous epithelial ovarian cancer genes as potential prognostic markers and indicators of the underlying molecular mechanisms using an integrated bioinformatics analysis.Oncol Lett. 2019 Nov;18(5):5508-5522. doi: 10.3892/ol.2019.10884. Epub 2019 Sep 19.
• [3] Comprehensive Analysis of Core Genes and Potential Mechanisms in Rectal Cancer.J Comput Biol. 2019 Nov;26(11):1262-1277. doi: 10.1089/cmb.2019.0073. Epub 2019 Jun 18.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] 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.
• [7] 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.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.