Details of Drug Off-Target (DOT)

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

• DOT Name: cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B)
• Gene Name: PRKAR2B
• UniProt ID: KAP3_HUMAN
• Pfam ID: PF00027 ; PF02197
• Sequence:
  MSIEIPAGLTELLQGFTVEVLRHQPADLLEFALQHFTRLQQENERKGTARFGHEGRTWGD
  LGAAAGGGTPSKGVNFAEEPMQSDSEDGEEEEAAPADAGAFNAPVINRFTRRASVCAEAY
  NPDEEEDDAESRIIHPKTDDQRNRLQEACKDILLFKNLDPEQMSQVLDAMFEKLVKDGEH
  VIDQGDDGDNFYVIDRGTFDIYVKCDGVGRCVGNYDNRGSFGELALMYNTPRAATITATS
  PGALWGLDRVTFRRIIVKNNAKKRKMYESFIESLPFLKSLEFSERLKVVDVIGTKVYNDG
  EQIIAQGDSADSFFIVESGEVKITMKRKGKSEVEENGAVEIARCSRGQYFGELALVTNKP
  RAASAHAIGTVKCLAMDVQAFERLLGPCMEIMKRNIATYEEQLVALFGTNMDIVEPTA
• Function: Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.
• Tissue Specificity: Four types of regulatory chains are found: I-alpha, I-beta, II-alpha, and II-beta. Their expression varies among tissues and is in some cases constitutive and in others inducible.
• KEGG Pathway: Insulin sig.ling pathway (hsa04910)
• Reactome Pathway:
  PKA activation in glucagon signalling (R-HSA-164378)
  DARPP-32 events (R-HSA-180024)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  CREB1 phosphorylation through the activation of Adenylate Cyclase (R-HSA-442720)
  Hedgehog 'off' state (R-HSA-5610787)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  PKA activation (R-HSA-163615)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenytoin	DMNOKBV	Approved	cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) increases the Hypersensitivity ADR of Phenytoin.	[22]

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 cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[8]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the methylation of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[20]

19 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 cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[11]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[14]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[18]
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 cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[19]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B).	[21]

References

• [1] 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.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Long noncoding RNA TDRG1 aggravates doxorubicin-induced cardiomyopathy by binding with miR-873-5p to upregulate PRKAR2. Environ Toxicol. 2022 Aug;37(8):2072-2083. doi: 10.1002/tox.23551. Epub 2022 May 7.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [7] 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.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [15] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [16] 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.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] 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.
• [19] 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.
• [20] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.
• [21] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [22] Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.