Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOK0NYQ)

• DOT Name: Methyltransferase N6AMT1 (N6AMT1)
• Synonyms: HemK methyltransferase family member 2; M.HsaHemK2P; Lysine N-methyltransferase 9; EC 2.1.1.-; Methylarsonite methyltransferase N6AMT1; EC 2.1.1.-; Protein N(5)-glutamine methyltransferase; EC 2.1.1.-
• Gene Name: N6AMT1
• UniProt ID: N6MT1_HUMAN
• PDB ID: 6H1D; 6H1E; 6K0X; 6KHS; 6KMR; 6KMS; 6PED
• EC Number: 2.1.1.-
• Pfam ID: PF05175
• Sequence:
  MAGENFATPFHGHVGRGAFSDVYEPAEDTFLLLDALEAAAAELAGVEICLEVGSGSGVVS
  AFLASMIGPQALYMCTDINPEAAACTLETARCNKVHIQPVITDLVKGLLPRLTEKVDLLV
  FNPPYVVTPPQEVGSHGIEAAWAGGRNGREVMDRFFPLVPDLLSPRGLFYLVTIKENNPE
  EILKIMKTKGLQGTTALSRQAGQETLSVLKFTKS
• Function: Methyltransferase that can methylate proteins and, to a lower extent, arsenic. Catalytic subunit of a heterodimer with TRMT112, which monomethylates 'Lys-12' of histone H4 (H4K12me1), a modification present at the promoters of numerous genes encoding cell cycle regulators. Catalytic subunit of a heterodimer with TRMT112, which catalyzes N5-methylation of Glu residue of proteins with a Gly-Gln-Xaa-Xaa-Xaa-Arg motif. Methylates ETF1 on 'Gln-185'; ETF1 needs to be complexed to ERF3 in its GTP-bound form to be efficiently methylated. May also play a role in the modulation of arsenic-induced toxicity by mediating the conversion of monomethylarsonous acid (3+) into the less toxic dimethylarsonic acid. It however only plays a limited role in arsenic metabolism compared with AS3MT.
• Tissue Specificity: Widely expressed, with highest expression in parathyroid and pituitary glands, followed by adrenal gland and kidney, and lowest expression in leukocytes and mammary gland.
• Reactome Pathway:
  Eukaryotic Translation Termination (R-HSA-72764)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:ENSG00000156239-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Methyltransferase N6AMT1 (N6AMT1) increases the methylation of Arsenic.	[13]

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 Methyltransferase N6AMT1 (N6AMT1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Methyltransferase N6AMT1 (N6AMT1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Methyltransferase N6AMT1 (N6AMT1).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[11]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Methyltransferase N6AMT1 (N6AMT1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Methyltransferase N6AMT1 (N6AMT1).	[7]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [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] 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] 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.
• [7] 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.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] 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.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms and arsenic methylation in Andean women. Environ Health Perspect. 2013 Jul;121(7):797-803. doi: 10.1289/ehp.1206003. Epub 2013 May 10.