Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT777OHS)

• DOT Name: cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B)
• Gene Name: PRKAR1B
• Related Disease:
  Alzheimer disease
  Carney complex
  Dementia
  Frontotemporal dementia
  Marbach-Schaaf neurodevelopmental syndrome
  Parkinson disease
  Pick disease
  Gastrointestinal stromal tumour
  Varicose veins
  PRKAR1B-related neurodegenerative dementia with intermediate filaments
  Adrenal adenoma
  Primary pigmented nodular adrenocortical disease
• UniProt ID: KAP1_HUMAN
• PDB ID: 4DIN; 4F9K
• Pfam ID: PF00027 ; PF02197
• Sequence:
  MASPPACPSEEDESLKGCELYVQLHGIQQVLKDCIVHLCISKPERPMKFLREHFEKLEKE
  ENRQILARQKSNSQSDSHDEEVSPTPPNPVVKARRRRGGVSAEVYTEEDAVSYVRKVIPK
  DYKTMTALAKAISKNVLFAHLDDNERSDIFDAMFPVTHIAGETVIQQGNEGDNFYVVDQG
  EVDVYVNGEWVTNISEGGSFGELALIYGTPRAATVKAKTDLKLWGIDRDSYRRILMGSTL
  RKRKMYEEFLSKVSILESLEKWERLTVADALEPVQFEDGEKIVVQGEPGDDFYIITEGTA
  SVLQRRSPNEEYVEVGRLGPSDYFGEIALLLNRPRAATVVARGPLKCVKLDRPRFERVLG
  PCSEILKRNIQRYNSFISLTV
• Function: Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.
• 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)
  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)
  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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Carney complex	DISVL3IP	Strong	Genetic Variation	[2]
Dementia	DISXL1WY	Strong	Genetic Variation	[1]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[3]
Marbach-Schaaf neurodevelopmental syndrome	DIS9T3AO	Strong	Autosomal dominant	[4]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Pick disease	DISP6X50	Strong	Biomarker	[3]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[5]
Varicose veins	DISIMBN2	moderate	Genetic Variation	[6]
PRKAR1B-related neurodegenerative dementia with intermediate filaments	DISIB1GX	Supportive	Autosomal dominant	[3]
Adrenal adenoma	DISC2UN8	Limited	Genetic Variation	[7]
Primary pigmented nodular adrenocortical disease	DISXCNDR	Limited	Genetic Variation	[7]

8 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 cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[17]

5 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 cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B).	[12]

References

• [1] Mutation frequency of PRKAR1B and the major familial dementia genes in a Dutch early onset dementia cohort.J Neurol. 2014 Nov;261(11):2085-92. doi: 10.1007/s00415-014-7456-y. Epub 2014 Aug 10.
• [2] Haploinsufficiency at the protein kinase A RI alpha gene locus leads to fertility defects in male mice and men.Mol Endocrinol. 2006 Oct;20(10):2504-13. doi: 10.1210/me.2006-0060. Epub 2006 May 25.
• [3] PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology. Brain. 2014 May;137(Pt 5):1361-73. doi: 10.1093/brain/awu067. Epub 2014 Apr 9.
• [4] Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain. Genet Med. 2021 Aug;23(8):1465-1473. doi: 10.1038/s41436-021-01152-7. Epub 2021 Apr 8.
• [5] A Novel PRKAR1B-BRAF Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy.J Natl Compr Canc Netw. 2018 Mar;16(3):238-242. doi: 10.6004/jnccn.2017.7039.
• [6] Clinical and Genetic Determinants of Varicose Veins.Circulation. 2018 Dec 18;138(25):2869-2880. doi: 10.1161/CIRCULATIONAHA.118.035584.
• [7] cAMP pathway alterations from the cell surface to the nucleus in adrenocortical tumors.Endocr Res. 2002 Nov;28(4):765-75. doi: 10.1081/erc-120017071.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [15] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.