Details of Drug Off-Target (DOT)

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

• DOT Name: 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A)
• Synonyms: EC 3.1.4.53; DPDE2; PDE46; cAMP-specific phosphodiesterase 4A
• Gene Name: PDE4A
• UniProt ID: PDE4A_HUMAN
• PDB ID: 2QYK; 3I8V; 3TVX
• EC Number: 3.1.4.53
• Pfam ID: PF18100 ; PF00233
• Sequence:
  MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPIRIQQRGYSDSAERAERERQ
  PHRPIERADAMDTSDRPGLRTTRMSWPSSFHGTGTGSGGAGGGSSRRFEAENGPTPSPGR
  SPLDSQASPGLVLHAGAATSQRRESFLYRSDSDYDMSPKTMSRNSSVTSEAHAEDLIVTP
  FAQVLASLRSVRSNFSLLTNVPVPSNKRSPLGGPTPVCKATLSEETCQQLARETLEELDW
  CLEQLETMQTYRSVSEMASHKFKRMLNRELTHLSEMSRSGNQVSEYISTTFLDKQNEVEI
  PSPTMKEREKQQAPRPRPSQPPPPPVPHLQPMSQITGLKKLMHSNSLNNSNIPRFGVKTD
  QEELLAQELENLNKWGLNIFCVSDYAGGRSLTCIMYMIFQERDLLKKFRIPVDTMVTYML
  TLEDHYHADVAYHNSLHAADVLQSTHVLLATPALDAVFTDLEILAALFAAAIHDVDHPGV
  SNQFLINTNSELALMYNDESVLENHHLAVGFKLLQEDNCDIFQNLSKRQRQSLRKMVIDM
  VLATDMSKHMTLLADLKTMVETKKVTSSGVLLLDNYSDRIQVLRNMVHCADLSNPTKPLE
  LYRQWTDRIMAEFFQQGDRERERGMEISPMCDKHTASVEKSQVGFIDYIVHPLWETWADL
  VHPDAQEILDTLEDNRDWYYSAIRQSPSPPPEEESRGPGHPPLPDKFQFELTLEEEEEEE
  ISMAQIPCTAQEALTAQGLSGVEEALDATIAWEASPAQESLEVMAQEASLEAELEAVYLT
  QQAQSTGSAPVAPDEFSSREEFVVAVSHSSPSALALQSPLLPAWRTLSVSEHAPGLPGLP
  STAAEVEAQREHQAAKRACSACAGTFGEDTSALPAPGGGGSGGDPT
• Function: Hydrolyzes the second messenger 3',5'-cyclic AMP (cAMP), which is a key regulator of many important physiological processes; [Isoform 1]: Efficiently hydrolyzes cAMP; [Isoform 2]: Efficiently hydrolyzes cAMP; [Isoform 3]: Efficiently hydrolyzes cAMP. The phosphodiesterase activity is not affected by calcium, calmodulin or cyclic GMP (cGMP) levels. Does not hydrolyze cGMP; [Isoform 4]: Efficiently hydrolyzes cAMP; [Isoform 6]: Efficiently hydrolyzes cAMP; [Isoform 7]: Efficiently hydrolyzes cAMP.
• Tissue Specificity: .Expressed in lymphoid cell subsets including CD8-positive T cells and T-helper 2 cells. Expressed in dendritic cells.; [Isoform 2]: Highly expressed in liver, stomach, testis, thyroid and adrenal glands and at a lower extent in placenta, kidney, pancreas, ovary, uterus and skin. Expressed in myeloid cell subsets including dendritic cells, monocytes, macrophages, eosinophils and mast cells. Expressed in natural killer cells. Expressed in bronchial smooth muscle.; [Isoform 6]: Expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes.; [Isoform 7]: Expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Found in specific neuronal subpopulations including cortical pyramidal neurons, horn neurons in the spinal cord and Purkinje cells in cerebellum (at protein level).
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cAMP sig.ling pathway (hsa04024)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  DARPP-32 events (R-HSA-180024)

Molecular Interaction Atlas (MIA) of This DOT

4 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 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[12]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[14]

11 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 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[7]
Roflumilast	DMPGHY8	Approved	Roflumilast decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[11]
Trequinsin	DMQRSMD	Terminated	Trequinsin decreases the activity of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 3',5'-cyclic-AMP phosphodiesterase 4A (PDE4A).	[13]

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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4578-83.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.