Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCRN5TB)

• DOT Name: 2',5'-phosphodiesterase 12 (PDE12)
• Synonyms: 2'-PDE; 2-PDE; EC 3.1.4.-; Mitochondrial deadenylase; EC 3.1.13.4
• Gene Name: PDE12
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Respiratory syncytial virus infection
• UniProt ID: PDE12_HUMAN
• PDB ID: 4Z0V; 4Z2B; 4ZKF
• EC Number: 3.1.13.4; 3.1.4.-
• Pfam ID: PF03372 ; PF21171
• Sequence:
  MWRLPGARAALRVIRTAVEKLSRAEAGSQTAAGAMERAVVRCVPSEPKLSLSFALADGSH
  KNMQRDQSEPLGRVLSRIATNALKGHAKAAAAKKSRKSRPNASGGAACSGPGPEPAVFCE
  PVVKLYYREEAVAEDVLNVDAWQDGAVLQIGDVKYKVERNPPAFTELQLPRYIMAGFPVC
  PKLSLEFGDPASSLFRWYKEAKPGAAEPEVGVPSSLSPSSPSSSWTETDVEERVYTPSNA
  DIGLRLKLHCTPGDGQRFGHSRELESVCVVEAGPGTCTFDHRHLYTKKVTEDALIRTVSY
  NILADTYAQTEFSRTVLYPYCAPYALELDYRQNLIQKELTGYNADVICLQEVDRAVFSDS
  LVPALEAFGLEGVFRIKQHEGLATFYRKSKFSLLSQHDISFYEALESDPLHKELLEKLVL
  YPSAQEKVLQRSSVLQVSVLQSTKDSSKRICVANTHLYWHPKGGYIRLIQMAVALAHIRH
  VSCDLYPGIPVIFCGDFNSTPSTGMYHFVINGSIPEDHEDWASNGEEERCNMSLTHFFKL
  KSACGEPAYTNYVGGFHGCLDYIFIDLNALEVEQVIPLPSHEEVTTHQALPSVSHPSDHI
  ALVCDLKWK
• Function: Enzyme that cleaves 2',5'-phosphodiester bond linking adenosines of the 5'-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system. Degrades triphosphorylated 2-5A to produce AMP and ATP. Also cleaves 3',5'-phosphodiester bond of oligoadenylates. Plays a role as a negative regulator of the 2-5A system that is one of the major pathways for antiviral and antitumor functions induced by interferons (IFNs). Suppression of this enzyme increases cellular 2-5A levels and decreases viral replication in cultured small-airway epithelial cells and Hela cells.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: OAS antiviral response (R-HSA-8983711)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Respiratory syncytial virus infection	DIS7FWHY	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 2',5'-phosphodiesterase 12 (PDE12).	[10]

References

• [1] Characterization of inhibitors of phosphodiesterase 1C on a human cellular system.FEBS J. 2007 Sep;274(18):4812-24. doi: 10.1111/j.1742-4658.2007.06001.x. Epub 2007 Aug 14.
• [2] The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors.J Biol Chem. 2015 Aug 7;290(32):19681-96. doi: 10.1074/jbc.M115.653113. Epub 2015 Jun 8.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.