Details of Drug Off-Target (DOT)

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

• DOT Name: Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4)
• Synonyms: EC 3.6.1.29; AP3A hydrolase; AP3Aase; Ectonucleotide pyrophosphatase/phosphodiesterase family member 4; E-NPP 4; NPP-4
• Gene Name: ENPP4
• UniProt ID: ENPP4_HUMAN
• PDB ID: 4LQY; 4LR2
• EC Number: 3.6.1.29
• Pfam ID: PF01663
• Sequence:
  MKLLVILLFSGLITGFRSDSSSSLPPKLLLVSFDGFRADYLKNYEFPHLQNFIKEGVLVE
  HVKNVFITKTFPNHYSIVTGLYEESHGIVANSMYDAVTKKHFSDSNDKDPFWWNEAVPIW
  VTNQLQENRSSAAAMWPGTDVPIHDTISSYFMNYNSSVSFEERLNNITMWLNNSNPPVTF
  ATLYWEEPDASGHKYGPEDKENMSRVLKKIDDLIGDLVQRLKMLGLWENLNVIITSDHGM
  TQCSQDRLINLDSCIDHSYYTLIDLSPVAAILPKINRTEVYNKLKNCSPHMNVYLKEDIP
  NRFYYQHNDRIQPIILVADEGWTIVLNESSQKLGDHGYDNSLPSMHPFLAAHGPAFHKGY
  KHSTINIVDIYPMMCHILGLKPHPNNGTFGHTKCLLVDQWCINLPEAIAIVIGSLLVLTM
  LTCLIIIMQNRLSVPRPFSRLQLQEDDDDPLIG
• Function: Hydrolyzes extracellular Ap3A into AMP and ADP, and Ap4A into AMP and ATP. Ap3A and Ap4A are diadenosine polyphosphates thought to induce proliferation of vascular smooth muscle cells. Acts as a procoagulant, mediating platelet aggregation at the site of nascent thrombus via release of ADP from Ap3A and activation of ADP receptors.
• Tissue Specificity: Expressed on the surface of vascular endothelia.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

7 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 Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[9]

3 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 Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Bis(5'-adenosyl)-triphosphatase ENPP4 (ENPP4).	[8]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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] 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.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.