Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN8035R)

• DOT Name: N-lysine methyltransferase SMYD2 (SMYD2)
• Synonyms: EC 2.1.1.-; HSKM-B; Histone methyltransferase SMYD2; EC 2.1.1.354; Lysine N-methyltransferase 3C; SET and MYND domain-containing protein 2
• Gene Name: SMYD2
• UniProt ID: SMYD2_HUMAN
• PDB ID: 3RIB; 3S7B; 3S7D; 3S7F; 3S7J; 3TG4; 3TG5; 4O6F; 4WUY; 4YND; 5ARF; 5ARG; 5KJK; 5KJL; 5KJM; 5KJN; 5V3H; 5WCG; 6CBX; 6CBY; 6MON; 6N3G
• EC Number: 2.1.1.-; 2.1.1.354
• Pfam ID: PF00856 ; PF01753
• Sequence:
  MRAEGLGGLERFCSPGKGRGLRALQPFQVGDLLFSCPAYAYVLTVNERGNHCEYCFTRKE
  GLSKCGRCKQAFYCNVECQKEDWPMHKLECSPMVVFGENWNPSETVRLTARILAKQKIHP
  ERTPSEKLLAVKEFESHLDKLDNEKKDLIQSDIAALHHFYSKHLGFPDNDSLVVLFAQVN
  CNGFTIEDEELSHLGSAIFPDVALMNHSCCPNVIVTYKGTLAEVRAVQEIKPGEEVFTSY
  IDLLYPTEDRNDRLRDSYFFTCECQECTTKDKDKAKVEIRKLSDPPKAEAIRDMVRYARN
  VIEEFRRAKHYKSPSELLEICELSQEKMSSVFEDSNVYMLHMMYQAMGVCLYMQDWEGAL
  QYGQKIIKPYSKHYPLYSLNVASMWLKLGRLYMGLEHKAAGEKALKKAIAIMEVAHGKDH
  PYISEIKQEIESH
• Function: Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. Specifically trimethylates histone H3 'Lys-4' (H3K4me3) in vivo. The activity requires interaction with HSP90alpha. Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:ENSG00000143499-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 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 N-lysine methyltransferase SMYD2 (SMYD2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[12]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of N-lysine methyltransferase SMYD2 (SMYD2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ademetionine	DMYQDBO	Approved	Ademetionine affects the binding of N-lysine methyltransferase SMYD2 (SMYD2).	[14]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells. Curr Genomics. 2019 May;20(4):260-274. doi: 10.2174/1389202920666190603123040.
• [8] 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.
• [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] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] 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.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
• [14] Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011 Sep 7;19(9):1262-73.
• [15] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.