Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2MNW8T)

• DOT Name: Pleckstrin homology domain-containing family A member 5 (PLEKHA5)
• Synonyms: PH domain-containing family A member 5; Phosphoinositol 3-phosphate-binding protein 2; PEPP-2
• Gene Name: PLEKHA5
• UniProt ID: PKHA5_HUMAN
• PDB ID: 2DKP
• Pfam ID: PF00169 ; PF00397
• Sequence:
  MAADLNLEWISLPRSWTYGITRGGRVFFINEEAKSTTWLHPVTGEAVVTGHRRQSTDLPT
  GWEEAYTFEGARYYINHNERKVTCKHPVTGQPSQDNCIFVVNEQTVATMTSEEKKERPIS
  MINEASNYNVTSDYAVHPMSPVGRTSRASKKVHNFGKRSNSIKRNPNAPVVRRGWLYKQD
  STGMKLWKKRWFVLSDLCLFYYRDEKEEGILGSILLPSFQIALLTSEDHINRKYAFKAAH
  PNMRTYYFCTDTGKEMELWMKAMLDAALVQTEPVKRVDKITSENAPTKETNNIPNHRVLI
  KPEIQNNQKNKEMSKIEEKKALEAEKYGFQKDGQDRPLTKINSVKLNSLPSEYESGSACP
  AQTVHYRPINLSSSENKIVNVSLADLRGGNRPNTGPLYTEADRVIQRTNSMQQLEQWIKI
  QKGRGHEEETRGVISYQTLPRNMPSHRAQIMARYPEGYRTLPRNSKTRPESICSVTPSTH
  DKTLGPGAEEKRRSMRDDTMWQLYEWQQRQFYNKQSTLPRHSTLSSPKTMVNISDQTMHS
  IPTSPSHGSIAAYQGYSPQRTYRSEVSSPIQRGDVTIDRRHRAHHPKHVYVPDRRSVPAG
  LTLQSVSPQSLQGKTLSQDEGRGTLYKYRPEEVDIDAKLSRLCEQDKVVHALEEKLQQLH
  KEKYTLEQALLSASQEIEMHADNPAAIQTVVLQRDDLQNGLLSTCRELSRATAELERAWR
  EYDKLEYDVTVTRNQMQEQLDHLGEVQTESAGIQRAQIQKELWRIQDVMEGLSKHKQQRG
  TTEIGMIGSKPFSTVKYKNEGPDYRLYKSEPELTTVAEVDESNGEEKSEPVSEIETSVVK
  GSHFPVGVVPPRAKSPTPESSTIASYVTLRKTKKMMDLRTERPRSAVEQLCLAESTRPRM
  TVEEQMERIRRHQQACLREKKKGLNVIGASDQSPLQSPSNLRDNPFRTTQTRRRDDKELD
  TAIRENDVKPDHETPATEIVQLKETEPQNVDFSKELKKTENISYEMLFEPEPNGVNSVEM
  MDKERNKDKMPEDVTFSPQDETQTANHKPEEHPEENTKNSVDEQEETVISYESTPEVSRG
  NQTMAVKSLSPSPESSASPVPSTQPQLTEGSHFMCV
• Tissue Specificity: Highly expressed in heart and kidney.
• Reactome Pathway: Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

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 Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[12]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[13]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Pleckstrin homology domain-containing family A member 5 (PLEKHA5).	[20]

References

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• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] 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.
• [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] 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.
• [6] 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.
• [7] 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.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] 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.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [14] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] 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.