Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNLWD0N)

• DOT Name: Arsenite methyltransferase (AS3MT)
• Synonyms: EC 2.1.1.137; Methylarsonite methyltransferase; S-adenosyl-L-methionine:arsenic(III) methyltransferase
• Gene Name: AS3MT
• UniProt ID: AS3MT_HUMAN
• EC Number: 2.1.1.137
• Pfam ID: PF13847
• Sequence:
  MAALRDAEIQKDVQTYYGQVLKRSADLQTNGCVTTARPVPKHIREALQNVHEEVALRYYG
  CGLVIPEHLENCWILDLGSGSGRDCYVLSQLVGEKGHVTGIDMTKGQVEVAEKYLDYHME
  KYGFQASNVTFIHGYIEKLGEAGIKNESHDIVVSNCVINLVPDKQQVLQEAYRVLKHGGE
  LYFSDVYTSLELPEEIRTHKVLWGECLGGALYWKELAVLAQKIGFCPPRLVTANLITIQN
  KELERVIGDCRFVSATFRLFKHSKTGPTKRCQVIYNGGITGHEKELMFDANFTFKEGEIV
  EVDEETAAILKNSRFAQDFLIRPIGEKLPTSGGCSALELKDIITDPFKLAEESDSMKSRC
  VPDAAGGCCGTKKSC
• Function: Catalyzes the transfer of a methyl group from AdoMet to trivalent arsenicals producing methylated and dimethylated arsenicals. It methylates arsenite to form methylarsonate, Me-AsO(3)H(2), which is reduced by methylarsonate reductase to methylarsonite, Me-As(OH)2. Methylarsonite is also a substrate and it is converted into the much less toxic compound dimethylarsinate (cacodylate), Me(2)As(O)-OH.
• KEGG Pathway: Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway: Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS01822-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	Arsenite methyltransferase (AS3MT) increases the methylation of Arsenic.	[17]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ademetionine	DMYQDBO	Approved	Arsenite methyltransferase (AS3MT) affects the binding of Ademetionine.	[8]

12 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 Arsenite methyltransferase (AS3MT).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Arsenite methyltransferase (AS3MT).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Arsenite methyltransferase (AS3MT).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Arsenite methyltransferase (AS3MT).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Arsenite methyltransferase (AS3MT).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Arsenite methyltransferase (AS3MT).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the splicing of Arsenite methyltransferase (AS3MT).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Arsenite methyltransferase (AS3MT).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Arsenite methyltransferase (AS3MT).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Arsenite methyltransferase (AS3MT).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Arsenite methyltransferase (AS3MT).	[15]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide increases the expression of Arsenite methyltransferase (AS3MT).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Glutathione affects the folding of Arsenite methyltransferase (AS3MT).	[8]

4 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 affects the methylation of Arsenite methyltransferase (AS3MT).	[10]
L-Cysteine	DMCMOS8	Clinical trial	L-Cysteine increases the reduction of Arsenite methyltransferase (AS3MT).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Arsenite methyltransferase (AS3MT).	[14]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the reduction of Arsenite methyltransferase (AS3MT).	[12]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] AS3MT facilitates NLRP3 inflammasome activation by m(6)A modification during arsenic-induced hepatic insulin resistance. Cell Biol Toxicol. 2023 Oct;39(5):2165-2181. doi: 10.1007/s10565-022-09703-7. Epub 2022 Feb 28.
• [7] Hydrogen peroxide triggers a novel alternative splicing of arsenic (+3?oxidation state) methyltransferase gene. Biochem Biophys Res Commun. 2016 Nov 4;480(1):18-22. doi: 10.1016/j.bbrc.2016.10.016. Epub 2016 Oct 6.
• [8] Rapid equilibrium kinetic analysis of arsenite methylation catalyzed by recombinant human arsenic (+3 oxidation state) methyltransferase (hAS3MT). J Biol Chem. 2012 Nov 9;287(46):38790-9. doi: 10.1074/jbc.M112.368050. Epub 2012 Sep 6.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [12] The functions of crucial cysteine residues in the arsenite methylation catalyzed by recombinant human arsenic (III) methyltransferase. PLoS One. 2014 Oct 28;9(10):e110924. doi: 10.1371/journal.pone.0110924. eCollection 2014.
• [13] 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.
• [14] 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.
• [15] Gene expression profiling analysis of bisphenol A-induced perturbation in biological processes in ER-negative HEK293 cells. PLoS One. 2014 Jun 5;9(6):e98635.
• [16] Involvement of a AS3MT/c-Fos/p53 signaling axis in arsenic-induced tumor in human lung cells. Environ Toxicol. 2023 Mar;38(3):615-627. doi: 10.1002/tox.23708. Epub 2022 Nov 18.
• [17] High arsenic metabolic efficiency in AS3MT287Thr allele carriers. Pharmacogenet Genomics. 2008 Apr;18(4):349-55. doi: 10.1097/FPC.0b013e3282f7f46b.