Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5VWYPI)

• DOT Name: Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C)
• Synonyms: Cam-PDE 1C; EC 3.1.4.17; Hcam3
• Gene Name: PDE1C
• Related Disease:
  Autosomal dominant nonsyndromic hearing loss
  Hearing loss, autosomal dominant 74
• UniProt ID: PDE1C_HUMAN
• EC Number: 3.1.4.17
• Pfam ID: PF00233 ; PF08499
• Sequence:
  MESPTKEIEEFESNSLKYLQPEQIEKIWLRLRGLRKYKKTSQRLRSLVKQLERGEASVVD
  LKKNLEYAATVLESVYIDETRRLLDTEDELSDIQSDAVPSEVRDWLASTFTRQMGMMLRR
  SDEKPRFKSIVHAVQAGIFVERMYRRTSNMVGLSYPPAVIEALKDVDKWSFDVFSLNEAS
  GDHALKFIFYELLTRYDLISRFKIPISALVSFVEALEVGYSKHKNPYHNLMHAADVTQTV
  HYLLYKTGVANWLTELEIFAIIFSAAIHDYEHTGTTNNFHIQTRSDPAILYNDRSVLENH
  HLSAAYRLLQDDEEMNILINLSKDDWREFRTLVIEMVMATDMSCHFQQIKAMKTALQQPE
  AIEKPKALSLMLHTADISHPAKAWDLHHRWTMSLLEEFFRQGDREAELGLPFSPLCDRKS
  TMVAQSQVGFIDFIVEPTFTVLTDMTEKIVSPLIDETSQTGGTGQRRSSLNSISSSDAKR
  SGVKTSGSEGSAPINNSVISVDYKSFKATWTEVVHINRERWRAKVPKEEKAKKEAEEKAR
  LAAEEQQKEMEAKSQAEEGASGKAEKKTSGETKNQVNGTRANKSDNPRGKNSKAEKSSGE
  QQQNGDFKDGKNKTDKKDHSNIGNDSKKTDGTKQRSHGSPAPSTSSTCRLTLPVIKPPLR
  HFKRPAYASSSYAPSVSKKTDEHPARYKMLDQRIKMKKIQNISHNWNRK
• Function: Calmodulin-dependent 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 high affinity for both cAMP and cGMP. Modulates the amplitude and duration of the cAMP signal in sensory cilia in response to odorant stimulation, hence contributing to the generation of action potentials. Regulates smooth muscle cell proliferation. Regulates the stability of growth factor receptors, including PDGFRB (Probable).
• Tissue Specificity: Isoform PDE1C2 is present in the heart and brain and, at lower levels in the lung, liver, kidney and skeletal muscle . Isoform PDE1C1 is expressed in the heart and brain and, at lower levels in lung . Also expressed at low levels in uterus and testis .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  Olfactory transduction (hsa04740)
  Taste transduction (hsa04742)
  Renin secretion (hsa04924)
  Morphine addiction (hsa05032)
• Reactome Pathway: Cam-PDE 1 activation (R-HSA-111957)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[1]
Hearing loss, autosomal dominant 74	DISFBQTO	Limited	Autosomal dominant	[2]

2 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 Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C (PDE1C).	[13]

References

• [1] A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss. Hum Genet. 2018 Jul;137(6-7):437-446. doi: 10.1007/s00439-018-1895-y. Epub 2018 Jun 2.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [11] 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.
• [12] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.