Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9YR20G)

• DOT Name: Histone-lysine N-methyltransferase SMYD3 (SMYD3)
• Synonyms: EC 2.1.1.354; SET and MYND domain-containing protein 3; Zinc finger MYND domain-containing protein 1
• Gene Name: SMYD3
• UniProt ID: SMYD3_HUMAN
• PDB ID: 3MEK ; 3OXF ; 3OXG ; 3OXL ; 3PDN ; 3QWP ; 3RU0 ; 5CCL ; 5CCM ; 5EX0 ; 5EX3 ; 5HI7 ; 5HQ8 ; 5V37 ; 5XXD ; 5XXG ; 5XXJ ; 5YJO ; 6IJL ; 6O9O ; 6P6G ; 6P6K ; 6P7Z ; 6PAF ; 6YUH ; 6ZRB ; 7BJ1 ; 7O2A ; 7O2B ; 7O2C ; 7QLB ; 7QNR ; 7QNU ; 8OWO
• EC Number: 2.1.1.354
• Pfam ID: PF00856 ; PF01753
• Sequence:
  MEPLKVEKFATAKRGNGLRAVTPLRPGELLFRSDPLAYTVCKGSRGVVCDRCLLGKEKLM
  RCSQCRVAKYCSAKCQKKAWPDHKRECKCLKSCKPRYPPDSVRLLGRVVFKLMDGAPSES
  EKLYSFYDLESNINKLTEDKKEGLRQLVMTFQHFMREEIQDASQLPPAFDLFEAFAKVIC
  NSFTICNAEMQEVGVGLYPSISLLNHSCDPNCSIVFNGPHLLLRAVRDIEVGEELTICYL
  DMLMTSEERRKQLRDQYCFECDCFRCQTQDKDADMLTGDEQVWKEVQESLKKIEELKAHW
  KWEQVLAMCQAIISSNSERLPDINIYQLKVLDCAMDACINLGLLEEALFYGTRTMEPYRI
  FFPGSHPVRGVQVMKVGKLQLHQGMFPQAMKNLRLAFDIMRVTHGREHSLIEDLILLLEE
  CDANIRAS
• Function: Histone methyltransferase. Specifically methylates 'Lys-4' of histone H3, inducing di- and tri-methylation, but not monomethylation. Also methylates 'Lys-5' of histone H4. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.
• Tissue Specificity: Expressed in skeletal muscles and testis. Overexpressed in a majority of colorectal and hepatocellular carcinomas.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS11979-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Histone-lysine N-methyltransferase SMYD3 (SMYD3) affects the response to substance of Acetaminophen.	[24]
Methamphetamine	DMPM4SK	Approved	Histone-lysine N-methyltransferase SMYD3 (SMYD3) affects the response to substance of Methamphetamine.	[25]

5 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 Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant affects the methylation of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[15]
Berberine	DMC5Q8X	Phase 4	Berberine affects the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[22]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Histone-lysine N-methyltransferase SMYD3 (SMYD3).	[23]

References

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• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] 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.
• [17] 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.
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• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] 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.
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• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Identification of early target genes of aflatoxin B1 in human hepatocytes, inter-individual variability and comparison with other genotoxic compounds. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):176-87.
• [24] 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.
• [25] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.