Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1FZVC9)

• DOT Name: m7GpppX diphosphatase (DCPS)
• Synonyms: EC 3.6.1.59; DCS-1; Decapping scavenger enzyme; Hint-related 7meGMP-directed hydrolase; Histidine triad nucleotide-binding protein 5; Histidine triad protein member 5; HINT-5; Scavenger mRNA-decapping enzyme DcpS
• Gene Name: DCPS
• Related Disease:
  Al-Raqad syndrome
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: DCPS_HUMAN
• PDB ID: 1ST0; 1ST4; 1XML; 1XMM; 3BL7; 3BL9; 3BLA; 4QDE; 4QDV; 4QEB; 5OSY
• EC Number: 3.6.1.59
• Pfam ID: PF05652 ; PF11969
• Sequence:
  MADAAPQLGKRKRELDVEEAHAASTEEKEAGVGNGTCAPVRLPFSGFRLQKVLRESARDK
  IIFLHGKVNEASGDGDGEDAVVILEKTPFQVEQVAQLLTGSPELQLQFSNDIYSTYHLFP
  PRQLNDVKTTVVYPATEKHLQKYLRQDLRLIRETGDDYRNITLPHLESQSLSIQWVYNIL
  DKKAEADRIVFENPDPSDGFVLIPDLKWNQQQLDDLYLIAICHRRGIRSLRDLTPEHLPL
  LRNILHQGQEAILQRYRMKGDHLRVYLHYLPSYYHLHVHFTALGFEAPGSGVERAHLLAE
  VIENLECDPRHYQQRTLTFALRADDPLLKLLQEAQQS
• Function: Decapping scavenger enzyme that catalyzes the cleavage of a residual cap structure following the degradation of mRNAs by the 3'->5' exosome-mediated mRNA decay pathway. Hydrolyzes cap analog structures like 7-methylguanosine nucleoside triphosphate (m7GpppG) with up to 10 nucleotide substrates (small capped oligoribonucleotides) and specifically releases 5'-phosphorylated RNA fragments and 7-methylguanosine monophosphate (m7GMP). Cleaves cap analog structures like tri-methyl guanosine nucleoside triphosphate (m3(2,2,7)GpppG) with very poor efficiency. Does not hydrolyze unmethylated cap analog (GpppG) and shows no decapping activity on intact m7GpppG-capped mRNA molecules longer than 25 nucleotides. Does not hydrolyze 7-methylguanosine diphosphate (m7GDP) to m7GMP. May also play a role in the 5'->3 mRNA decay pathway; m7GDP, the downstream product released by the 5'->3' mRNA mediated decapping activity, may be also converted by DCPS to m7GMP. Binds to m7GpppG and strongly to m7GDP. Plays a role in first intron splicing of pre-mRNAs. Inhibits activation-induced cell death.
• Tissue Specificity: Detected in liver, brain, kidney, testis and prostate.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway: mRNA decay by 3' to 5' exoribonuclease (R-HSA-429958)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Al-Raqad syndrome	DISR2J8Q	Strong	Autosomal recessive	[1]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	m7GpppX diphosphatase (DCPS) affects the response to substance of Vinblastine.	[19]

14 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 m7GpppX diphosphatase (DCPS).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of m7GpppX diphosphatase (DCPS).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of m7GpppX diphosphatase (DCPS).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of m7GpppX diphosphatase (DCPS).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of m7GpppX diphosphatase (DCPS).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of m7GpppX diphosphatase (DCPS).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of m7GpppX diphosphatase (DCPS).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of m7GpppX diphosphatase (DCPS).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of m7GpppX diphosphatase (DCPS).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of m7GpppX diphosphatase (DCPS).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of m7GpppX diphosphatase (DCPS).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of m7GpppX diphosphatase (DCPS).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of m7GpppX diphosphatase (DCPS).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of m7GpppX diphosphatase (DCPS).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of m7GpppX diphosphatase (DCPS).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of m7GpppX diphosphatase (DCPS).	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of m7GpppX diphosphatase (DCPS).	[13]

References

• [1] Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. Hum Mol Genet. 2015 Jun 1;24(11):3172-80. doi: 10.1093/hmg/ddv069. Epub 2015 Feb 20.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [14] 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.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] 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.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.