Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH2KILE)

• DOT Name: Protein arginine N-methyltransferase 3 (PRMT3)
• Synonyms: EC 2.1.1.319; Heterogeneous nuclear ribonucleoprotein methyltransferase-like protein 3
• Gene Name: PRMT3
• UniProt ID: ANM3_HUMAN
• PDB ID: 2FYT; 3SMQ; 4HSG; 4QQN; 4RYL; 8G2F; 8G2G
• EC Number: 2.1.1.319
• Pfam ID: PF21137 ; PF21336 ; PF06325
• Sequence:
  MCSLASGATGGRGAVENEEDLPELSDSGDEAAWEDEDDADLPHGKQQTPCLFCNRLFTSA
  EETFSHCKSEHQFNIDSMVHKHGLEFYGYIKLINFIRLKNPTVEYMNSIYNPVPWEKEEY
  LKPVLEDDLLLQFDVEDLYEPVSVPFSYPNGLSENTSVVEKLKHMEARALSAEAALARAR
  EDLQKMKQFAQDFVMHTDVRTCSSSTSVIADLQEDEDGVYFSSYGHYGIHEEMLKDKIRT
  ESYRDFIYQNPHIFKDKVVLDVGCGTGILSMFAAKAGAKKVLGVDQSEILYQAMDIIRLN
  KLEDTITLIKGKIEEVHLPVEKVDVIISEWMGYFLLFESMLDSVLYAKNKYLAKGGSVYP
  DICTISLVAVSDVNKHADRIAFWDDVYGFKMSCMKKAVIPEAVVEVLDPKTLISEPCGIK
  HIDCHTTSISDLEFSSDFTLKITRTSMCTAIAGYFDIYFEKNCHNRVVFSTGPQSTKTHW
  KQTVFLLEKPFSVKAGEALKGKVTVHKNKKDPRSLTVTLTLNNSTQTYGLQ
• Function: Protein-arginine N-methyltransferase that catalyzes both the monomethylation and asymmetric dimethylation of the guanidino nitrogens of arginine residues in target proteins, and therefore falls into the group of type I methyltransferases (Probable). May regulate retinoic acid synthesis and signaling by inhibiting ALDH1A1 retinal dehydrogenase activity.
• Reactome Pathway:
  Protein methylation (R-HSA-8876725)
  RMTs methylate histone arginines (R-HSA-3214858)
• BioCyc Pathway: MetaCyc:MONOMER66-43216

Molecular Interaction Atlas (MIA) of This DOT

12 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 3 (PRMT3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[5]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[6]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein arginine N-methyltransferase 3 (PRMT3).	[12]

1 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 Protein arginine N-methyltransferase 3 (PRMT3).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
SGC707	DMGINBT	Investigative	SGC707 affects the folding of Protein arginine N-methyltransferase 3 (PRMT3).	[13]

References

• [1] 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.
• [2] 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.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] 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.
• [7] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase (PRMT3). Angew Chem Int Ed Engl. 2015 Apr 20;54(17):5166-70.