Details of Drug Off-Target (DOT)

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

• DOT Name: Protein N-lysine methyltransferase METTL21A (METTL21A)
• Synonyms: EC 2.1.1.-; HSPA lysine methyltransferase; HSPA-KMT; Hepatocellular carcinoma-associated antigen 557b; Methyltransferase-like protein 21A
• Gene Name: METTL21A
• Related Disease: Amyotrophic lateral sclerosis type 1
• UniProt ID: MT21A_HUMAN
• PDB ID: 4LEC
• EC Number: 2.1.1.-
• Pfam ID: PF10294
• Sequence:
  MALVPYEETTEFGLQKFHKPLATFSFANHTIQIRQDWRHLGVAAVVWDAAIVLSTYLEMG
  AVELRGRSAVELGAGTGLVGIVAALLGAHVTITDRKVALEFLKSNVQANLPPHIQTKTVV
  KELTWGQNLGSFSPGEFDLILGADIIYLEETFTDLLQTLEHLCSNHSVILLACRIRYERD
  NNFLAMLERQFTVRKVHYDPEKDVHIYEAQKRNQKEDL
• Function: Protein-lysine methyltransferase that selectively trimethylates residues in heat shock protein 70 (HSP70) family members. Contributes to the in vivo trimethylation of Lys residues in HSPA1 and HSPA8. In vitro methylates 'Lys-561' in HSPA1, 'Lys-564' in HSPA2, 'Lys-585' in HSPA5, 'Lys-563' in HSPA6 and 'Lys-561' in HSPA8.
• Reactome Pathway: Protein methylation (R-HSA-8876725)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Limited	Genetic Variation	[1]

11 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 Protein N-lysine methyltransferase METTL21A (METTL21A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[10]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein N-lysine methyltransferase METTL21A (METTL21A).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein N-lysine methyltransferase METTL21A (METTL21A).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein N-lysine methyltransferase METTL21A (METTL21A).	[13]

References

• [1] Genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations.Neurobiol Aging. 2014 Jul;35(7):1778.e9-1778.e23. doi: 10.1016/j.neurobiolaging.2014.01.014. Epub 2014 Jan 17.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [14] 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.