Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6IGJS)

• DOT Name: Protein arginine N-methyltransferase 5 (PRMT5)
• Synonyms: PRMT5; EC 2.1.1.320; 72 kDa ICln-binding protein; Histone-arginine N-methyltransferase PRMT5; Jak-binding protein 1; Shk1 kinase-binding protein 1 homolog; SKB1 homolog; SKB1Hs
• Gene Name: PRMT5
• UniProt ID: ANM5_HUMAN
• PDB ID: 4GQB ; 4X60 ; 4X61 ; 4X63 ; 5C9Z ; 5EMJ ; 5EMK ; 5EML ; 5EMM ; 5FA5 ; 6CKC ; 6K1S ; 6RLL ; 6RLQ ; 6UGH ; 6UXX ; 6UXY ; 6V0N ; 6V0O ; 6V0P ; 7BO7 ; 7BOC ; 7KIB ; 7KIC ; 7KID ; 7L1G ; 7M05 ; 7MX7 ; 7MXA ; 7MXC ; 7MXG ; 7MXN ; 7S0U ; 7S1P ; 7S1Q ; 7S1R ; 7S1S ; 7SER ; 7SES ; 7U30 ; 7UOH ; 7UY1 ; 7UYF ; 7ZUP ; 7ZUQ ; 7ZUU ; 7ZUY ; 7ZV2 ; 7ZVL ; 7ZVU ; 8CSG ; 8CTB ; 8CYI ; 8G1U
• EC Number: 2.1.1.320
• Pfam ID: PF05185 ; PF17286 ; PF17285
• Sequence:
  MAAMAVGGAGGSRVSSGRDLNCVPEIADTLGAVAKQGFDFLCMPVFHPRFKREFIQEPAK
  NRPGPQTRSDLLLSGRDWNTLIVGKLSPWIRPDSKVEKIRRNSEAAMLQELNFGAYLGLP
  AFLLPLNQEDNTNLARVLTNHIHTGHHSSMFWMRVPLVAPEDLRDDIIENAPTTHTEEYS
  GEEKTWMWWHNFRTLCDYSKRIAVALEIGADLPSNHVIDRWLGEPIKAAILPTSIFLTNK
  KGFPVLSKMHQRLIFRLLKLEVQFIITGTNHHSEKEFCSYLQYLEYLSQNRPPPNAYELF
  AKGYEDYLQSPLQPLMDNLESQTYEVFEKDPIKYSQYQQAIYKCLLDRVPEEEKDTNVQV
  LMVLGAGRGPLVNASLRAAKQADRRIKLYAVEKNPNAVVTLENWQFEEWGSQVTVVSSDM
  REWVAPEKADIIVSELLGSFADNELSPECLDGAQHFLKDDGVSIPGEYTSFLAPISSSKL
  YNEVRACREKDRDPEAQFEMPYVVRLHNFHQLSAPQPCFTFSHPNRDPMIDNNRYCTLEF
  PVEVNTVLHGFAGYFETVLYQDITLSIRPETHSPGMFSWFPILFPIKQPITVREGQTICV
  RFWRCSNSKKVWYEWAVTAPVCSAIHNPTGRSYTIGL
• Function: Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H and may regulate its transcriptional elongation properties. May methylate the N-terminal region of MBD2. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter. Methylates GM130/GOLGA2, regulating Golgi ribbon formation. Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner. Symmetrically methylates POLR2A, a modification that allows the recruitment to POLR2A of proteins including SMN1/SMN2 and SETX. This is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. Along with LYAR, binds the promoter of gamma-globin HBG1/HBG2 and represses its expression. Symmetrically methylates NCL. Methylates p53/TP53; methylation might possibly affect p53/TP53 target gene specificity. Involved in spliceosome maturation and mRNA splicing in prophase I spermatocytes through the catalysis of the symmetrical arginine dimethylation of SNRPB (small nuclear ribonucleoprotein-associated protein) and the interaction with tudor domain-containing protein TDRD6.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  RMTs methylate histone arginines (R-HSA-3214858)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  snRNP Assembly (R-HSA-191859)
• BioCyc Pathway: MetaCyc:HS02092-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

23 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 Protein arginine N-methyltransferase 5 (PRMT5).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[11]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[12]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[15]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Protein arginine N-methyltransferase 5 (PRMT5).	[20]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the activity of Protein arginine N-methyltransferase 5 (PRMT5).	[21]
PP-242	DM2348V	Investigative	PP-242 increases the activity of Protein arginine N-methyltransferase 5 (PRMT5).	[21]
(L-)-S-adenosyl-L-homocysteine	DMDUN83	Investigative	(L-)-S-adenosyl-L-homocysteine decreases the activity of Protein arginine N-methyltransferase 5 (PRMT5).	[16]

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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] 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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [13] Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in diffuse large B-cell lymphoma. Haematologica. 2018 Dec;103(12):2049-2058. doi: 10.3324/haematol.2018.191684. Epub 2018 Aug 3.
• [14] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Ribavirin inhibits colorectal cancer growth by downregulating PRMT5 expression and H3R8me2s and H4R3me2s accumulation. Toxicol Appl Pharmacol. 2021 Mar 15;415:115450. doi: 10.1016/j.taap.2021.115450. Epub 2021 Feb 9.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [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] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [21] The protein arginine methyltransferase PRMT5 confers therapeutic resistance to mTOR inhibition in glioblastoma. J Neurooncol. 2019 Oct;145(1):11-22. doi: 10.1007/s11060-019-03274-0. Epub 2019 Aug 31.