Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVDV4IT)

• DOT Name: High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A)
• Synonyms: EC 3.1.4.53; HCP1; TM22; cAMP-specific phosphodiesterase 7A
• Gene Name: PDE7A
• UniProt ID: PDE7A_HUMAN
• PDB ID: 1ZKL; 3G3N; 4PM0; 4Y2B
• EC Number: 3.1.4.53
• Pfam ID: PF00233
• Sequence:
  MEVCYQLPVLPLDRPVPQHVLSRRGAISFSSSSALFGCPNPRQLSQRRGAISYDSSDQTA
  LYIRMLGDVRVRSRAGFESERRGSHPYIDFRIFHSQSEIEVSVSARNIRRLLSFQRYLRS
  SRFFRGTAVSNSLNILDDDYNGQAKCMLEKVGNWNFDIFLFDRLTNGNSLVSLTFHLFSL
  HGLIEYFHLDMMKLRRFLVMIQEDYHSQNPYHNAVHAADVTQAMHCYLKEPKLANSVTPW
  DILLSLIAAATHDLDHPGVNQPFLIKTNHYLATLYKNTSVLENHHWRSAVGLLRESGLFS
  HLPLESRQQMETQIGALILATDISRQNEYLSLFRSHLDRGDLCLEDTRHRHLVLQMALKC
  ADICNPCRTWELSKQWSEKVTEEFFHQGDIEKKYHLGVSPLCDRHTESIANIQIGFMTYL
  VEPLFTEWARFSNTRLSQTMLGHVGLNKASWKGLQREQSSSEDTDAAFELNSQLLPQENR
  LS
• Function: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May have a role in muscle signal transduction.
• Tissue Specificity: .Found at high levels in skeletal muscle and at low levels in a variety of tissues including brain and heart . It is expressed as well in two T-cell lines .; [Isoform PDE7A2]: Found abundantly in skeletal muscle and at low levels in heart.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Morphine addiction (hsa05032)
• Reactome Pathway: G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A) increases the hydrolysis of [3H]cAMP.	[12]

4 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 High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[9]

8 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 High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[4]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[6]
Roflumilast	DMPGHY8	Approved	Roflumilast decreases the activity of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[7]
Trequinsin	DMQRSMD	Terminated	Trequinsin decreases the activity of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[10]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of High affinity 3',5'-cyclic-AMP phosphodiesterase 7A (PDE7A).	[11]

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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] 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.
• [6] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [7] 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.
• [8] 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.
• [9] 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.
• [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 dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [12] Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):472-6. doi: 10.1073/pnas.97.1.472.