Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKUW1WT)

DOT Name cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A)
Synonyms EC 3.1.4.17; Cyclic GMP-inhibited phosphodiesterase A; CGI-PDE A; cGMP-inhibited cAMP phosphodiesterase; cGI-PDE
Gene Name PDE3A
Related Disease
Brachydactyly-arterial hypertension syndrome ( )
UniProt ID
PDE3A_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
7EG0; 7EG1; 7EG4; 7KWE; 7L27; 7L28; 7L29; 7LRC; 7LRD
EC Number
3.1.4.17
Pfam ID
PF00233
Sequence
MAVPGDAARVRDKPVHSGVSQAPTAGRDCHHRADPASPRDSGCRGCWGDLVLQPLRSSRK
LSSALCAGSLSFLLALLVRLVRGEVGCDLEQCKEAAAAEEEEAAPGAEGGVFPGPRGGAP
GGGARLSPWLQPSALLFSLLCAFFWMGLYLLRAGVRLPLAVALLAACCGGEALVQIGLGV
GEDHLLSLPAAGVVLSCLAAATWLVLRLRLGVLMIALTSAVRTVSLISLERFKVAWRPYL
AYLAGVLGILLARYVEQILPQSAEAAPREHLGSQLIAGTKEDIPVFKRRRRSSSVVSAEM
SGCSSKSHRRTSLPCIPREQLMGHSEWDHKRGPRGSQSSGTSITVDIAVMGEAHGLITDL
LADPSLPPNVCTSLRAVSNLLSTQLTFQAIHKPRVNPVTSLSENYTCSDSEESSEKDKLA
IPKRLRRSLPPGLLRRVSSTWTTTTSATGLPTLEPAPVRRDRSTSIKLQEAPSSSPDSWN
NPVMMTLTKSRSFTSSYAISAANHVKAKKQSRPGALAKISPLSSPCSSPLQGTPASSLVS
KISAVQFPESADTTAKQSLGSHRALTYTQSAPDLSPQILTPPVICSSCGRPYSQGNPADE
PLERSGVATRTPSRTDDTAQVTSDYETNNNSDSSDIVQNEDETECLREPLRKASACSTYA
PETMMFLDKPILAPEPLVMDNLDSIMEQLNTWNFPIFDLVENIGRKCGRILSQVSYRLFE
DMGLFEAFKIPIREFMNYFHALEIGYRDIPYHNRIHATDVLHAVWYLTTQPIPGLSTVIN
DHGSTSDSDSDSGFTHGHMGYVFSKTYNVTDDKYGCLSGNIPALELMALYVAAAMHDYDH
PGRTNAFLVATSAPQAVLYNDRSVLENHHAAAAWNLFMSRPEYNFLINLDHVEFKHFRFL
VIEAILATDLKKHFDFVAKFNGKVNDDVGIDWTNENDRLLVCQMCIKLADINGPAKCKEL
HLQWTDGIVNEFYEQGDEEASLGLPISPFMDRSAPQLANLQESFISHIVGPLCNSYDSAG
LMPGKWVEDSDESGDTDDPEEEEEEAPAPNEEETCENNESPKKKTFKRRKIYCQITQHLL
QNHKMWKKVIEEEQRLAGIENQSLDQTPQSHSSEQIQAIKEEEEEKGKPRGEEIPTQKPD
Q
Function
Cyclic nucleotide phosphodiesterase with specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has also activity toward cUMP. Independently of its catalytic activity it is part of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2 stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal RNA/rRNA ribonuclease activity. This apoptotic pathway might be relevant in tissues with high concentration of E2 and be for instance involved in placenta remodeling.
KEGG Pathway
Purine metabolism (hsa00230 )
Metabolic pathways (hsa01100 )
cGMP-PKG sig.ling pathway (hsa04022 )
cAMP sig.ling pathway (hsa04024 )
Renin secretion (hsa04924 )
Morphine addiction (hsa05032 )
Reactome Pathway
G alpha (s) signalling events (R-HSA-418555 )

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Brachydactyly-arterial hypertension syndrome DISATD9M Strong Autosomal dominant [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
5 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [2]
Arsenic DMTL2Y1 Approved Arsenic increases the methylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [6]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [13]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [16]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [17]
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18 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [3]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [4]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [5]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [7]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [8]
Testosterone DM7HUNW Approved Testosterone increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [7]
Panobinostat DM58WKG Approved Panobinostat increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [8]
Dasatinib DMJV2EK Approved Dasatinib increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [9]
Ethinyl estradiol DMODJ40 Approved Ethinyl estradiol decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [10]
Roflumilast DMPGHY8 Approved Roflumilast decreases the activity of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [11]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [8]
OTX-015 DMI8RG1 Phase 1/2 OTX-015 decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [12]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [14]
Mivebresib DMCPF90 Phase 1 Mivebresib decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [12]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [15]
Trequinsin DMQRSMD Terminated Trequinsin decreases the activity of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [11]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [8]
Sulforaphane DMQY3L0 Investigative Sulforaphane decreases the expression of cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A (PDE3A). [18]
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⏷ Show the Full List of 18 Drug(s)

References

1 PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet. 2015 Jun;47(6):647-53. doi: 10.1038/ng.3302. Epub 2015 May 11.
2 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.
3 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.
4 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
5 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.
6 Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
7 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
8 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.
9 Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
10 The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
11 Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors. J Pharmacol Exp Ther. 2005 Aug;314(2):846-54. doi: 10.1124/jpet.105.083519. Epub 2005 May 18.
12 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.
13 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.
14 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
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 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.
17 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.
18 Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.