Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN8GTXW)

• DOT Name: Protein arginine N-methyltransferase 1 (PRMT1)
• Synonyms: EC 2.1.1.319; Histone-arginine N-methyltransferase PRMT1; Interferon receptor 1-bound protein 4
• Gene Name: PRMT1
• UniProt ID: ANM1_HUMAN
• PDB ID: 6NT2
• EC Number: 2.1.1.319
• Pfam ID: PF13649
• Sequence:
  MAAAEAANCIMENFVATLANGMSLQPPLEEVSCGQAESSEKPNAEDMTSKDYYFDSYAHF
  GIHEEMLKDEVRTLTYRNSMFHNRHLFKDKVVLDVGSGTGILCMFAAKAGARKVIGIECS
  SISDYAVKIVKANKLDHVVTIIKGKVEEVELPVEKVDIIISEWMGYCLFYESMLNTVLYA
  RDKWLAPDGLIFPDRATLYVTAIEDRQYKDYKIHWWENVYGFDMSCIKDVAIKEPLVDVV
  DPKQLVTNACLIKEVDIYTVKVEDLTFTSPFCLQVKRNDYVHALVAYFNIEFTRCHKRTG
  FSTSPESPYTHWKQTVFYMEDYLTVKTGEEIFGTIGMRPNAKNNRDLDFTIDLDFKGQLC
  ELSCSTDYRMR
• Function: Arginine methyltransferase that methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues present in proteins such as ESR1, histone H2, H3 and H4, FMR1, ILF3, HNRNPA1, HNRNPD, NFATC2IP, SUPT5H, TAF15, EWS, HABP4, SERBP1, RBM15, FOXO1, CHTOP, MAP3K5/ASK1 and NPRL2. Constitutes the main enzyme that mediates monomethylation and asymmetric dimethylation of histone H4 'Arg-4' (H4R3me1 and H4R3me2a, respectively), a specific tag for epigenetic transcriptional activation. May be involved in the regulation of TAF15 transcriptional activity, act as an activator of estrogen receptor (ER)-mediated transactivation, play a key role in neurite outgrowth and act as a negative regulator of megakaryocytic differentiation, by modulating p38 MAPK pathway. Methylates RBM15, promoting ubiquitination and degradation of RBM15. Methylates FOXO1 and retains it in the nucleus increasing its transcriptional activity. Methylates CHTOP and this methylation is critical for its 5-hydroxymethylcytosine (5hmC)-binding activity. Methylates MAP3K5/ASK1 at 'Arg-78' and 'Arg-80' which promotes association of MAP3K5 with thioredoxin and negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 stimulation and MAP3K5-induced activation of JNK. Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner. Plays a role in regulating alternative splicing in the heart. Methylates NPRL2 at 'Arg-78' leading to inhibition of its GTPase activator activity and then the GATOR1 complex and consequently inducing timely mTORC1 activation under methionine-sufficient conditions.
• Tissue Specificity: Widely expressed . Expressed strongly in colorectal cancer cells (at protein level) . Expressed strongly in colorectal cancer tissues compared to wild-type colon samples (at protein level) . Expressed strongly in colorectal cancer tissues compared to wild-type colon samples .
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Glucagon sig.ling pathway (hsa04922)
• Reactome Pathway:
  TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest (R-HSA-6804114)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Maturation of nucleoprotein (R-HSA-9694631)
  RMTs methylate histone arginines (R-HSA-3214858)
• BioCyc Pathway: MetaCyc:HS05019-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Protein arginine N-methyltransferase 1 (PRMT1) affects the response to substance of Acetaminophen.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein arginine N-methyltransferase 1 (PRMT1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein arginine N-methyltransferase 1 (PRMT1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[9]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the activity of Protein arginine N-methyltransferase 1 (PRMT1).	[11]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[10]
Dapsone	DM4LT8A	Approved	Dapsone decreases the activity of Protein arginine N-methyltransferase 1 (PRMT1).	[12]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[8]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin affects the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Protein arginine N-methyltransferase 1 (PRMT1).	[19]
(L-)-S-adenosyl-L-homocysteine	DMDUN83	Investigative	(L-)-S-adenosyl-L-homocysteine decreases the activity of Protein arginine N-methyltransferase 1 (PRMT1).	[20]

References

• [1] 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.
• [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] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] 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.
• [9] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [10] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [11] The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Mol Pharmacol. 2005 Aug;68(2):551-8. doi: 10.1124/mol.105.012104. Epub 2005 May 23.
• [12] Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitors of the arginine methyltransferase hPRMT1. Bioorg Med Chem. 2011 Jun 15;19(12):3717-31. doi: 10.1016/j.bmc.2011.02.032. Epub 2011 Feb 27.
• [13] 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.
• [14] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [15] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [16] 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.
• [17] Ribavirin inhibits the growth and ascites formation of hepatocellular carcinoma through downregulation of type I CARM1 and type II PRMT5. Toxicol Appl Pharmacol. 2022 Jan 15;435:115829. doi: 10.1016/j.taap.2021.115829. Epub 2021 Dec 14.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [20] 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.
• [21] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.