Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZESF4H)

• DOT Name: cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A)
• Synonyms: EC 3.1.4.17; Cyclic GMP-stimulated phosphodiesterase; CGS-PDE; cGSPDE
• Gene Name: PDE2A
• Related Disease:
  Intellectual developmental disorder with paroxysmal dyskinesia or seizures
  Infantile convulsions and choreoathetosis
• UniProt ID: PDE2A_HUMAN
• PDB ID: 1Z1L ; 3IBJ ; 3ITM ; 3ITU ; 4C1I ; 4D08 ; 4D09 ; 4HTX ; 4HTZ ; 4JIB ; 5TZ3 ; 5TZA ; 5TZC ; 5TZH ; 5TZW ; 5TZX ; 5TZZ ; 5U00 ; 5U7D ; 5U7I ; 5U7J ; 5U7K ; 5U7L ; 5VP0 ; 5VP1 ; 5XKM ; 6B96 ; 6B97 ; 6B98 ; 6BLF ; 6C7D ; 6C7E ; 6C7F ; 6C7G ; 6C7I ; 6C7J ; 6CYB ; 6CYC ; 6CYD ; 6ZND ; 6ZQZ
• EC Number: 3.1.4.17
• Pfam ID: PF01590 ; PF00233
• Sequence:
  MGQACGHSILCRSQQYPAARPAEPRGQQVFLKPDEPPPPPQPCADSLQDALLSLGSVIDI
  SGLQRAVKEALSAVLPRVETVYTYLLDGESQLVCEDPPHELPQEGKVREAIISQKRLGCN
  GLGFSDLPGKPLARLVAPLAPDTQVLVMPLADKEAGAVAAVILVHCGQLSDNEEWSLQAV
  EKHTLVALRRVQVLQQRGPREAPRAVQNPPEGTAEDQKGGAAYTDRDRKILQLCGELYDL
  DASSLQLKVLQYLQQETRASRCCLLLVSEDNLQLSCKVIGDKVLGEEVSFPLTGCLGQVV
  EDKKSIQLKDLTSEDVQQLQSMLGCELQAMLCVPVISRATDQVVALACAFNKLEGDLFTD
  EDEHVIQHCFHYTSTVLTSTLAFQKEQKLKCECQALLQVAKNLFTHLDDVSVLLQEIITE
  ARNLSNAEICSVFLLDQNELVAKVFDGGVVDDESYEIRIPADQGIAGHVATTGQILNIPD
  AYAHPLFYRGVDDSTGFRTRNILCFPIKNENQEVIGVAELVNKINGPWFSKFDEDLATAF
  SIYCGISIAHSLLYKKVNEAQYRSHLANEMMMYHMKVSDDEYTKLLHDGIQPVAAIDSNF
  ASFTYTPRSLPEDDTSMAILSMLQDMNFINNYKIDCPTLARFCLMVKKGYRDPPYHNWMH
  AFSVSHFCYLLYKNLELTNYLEDIEIFALFISCMCHDLDHRGTNNSFQVASKSVLAALYS
  SEGSVMERHHFAQAIAILNTHGCNIFDHFSRKDYQRMLDLMRDIILATDLAHHLRIFKDL
  QKMAEVGYDRNNKQHHRLLLCLLMTSCDLSDQTKGWKTTRKIAELIYKEFFSQGDLEKAM
  GNRPMEMMDREKAYIPELQISFMEHIAMPIYKLLQDLFPKAAELYERVASNREHWTKVSH
  KFTIRGLPSNNSLDFLDEEYEVPDLDGTRAPINGCCSLDAE
• Function: cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a higher efficiency with cGMP compared to cAMP. Plays a role in cell growth and migration ; [Isoform PDE2A2]: Regulates mitochondrial cAMP levels and respiration. Involved in the regulation of mitochondria morphology/dynamics and apoptotic cell death via local modulation of cAMP/PKA signaling in the mitochondrion, including the monitoring of local cAMP levels at the outer mitochondrial membrane and of PKA-dependent phosphorylation of DNM1L.
• Tissue Specificity: Widely expressed . Expressed in brain, with high expression observed in the corpus striatum . Also expressed in heart, placenta, lung, skeletal muscle, kidney and pancreas .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cGMP-PKG sig.ling pathway (hsa04022)
  Olfactory transduction (hsa04740)
  Aldosterone synthesis and secretion (hsa04925)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual developmental disorder with paroxysmal dyskinesia or seizures	DISDAAFG	Strong	Autosomal recessive	[1]
Infantile convulsions and choreoathetosis	DIS0H0JE	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[13]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[14]
EXISULIND	DMBY56U	Phase 3	EXISULIND decreases the activity of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A).	[17]

References

• [1] A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea. Mov Disord. 2018 Mar;33(3):482-488. doi: 10.1002/mds.27286. Epub 2018 Feb 2.
• [2] Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia. Eur J Hum Genet. 2020 Oct;28(10):1403-1413. doi: 10.1038/s41431-020-0641-9. Epub 2020 May 28.
• [3] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] 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.
• [13] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [14] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [15] Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res. 2000 Jul 1;60(13):3338-42.
• [16] 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.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [19] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.