Details of Drug Off-Target (DOT)

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

• DOT Name: S-adenosylmethionine synthase isoform type-2 (MAT2A)
• Synonyms: AdoMet synthase 2; EC 2.5.1.6; Methionine adenosyltransferase 2; MAT 2; Methionine adenosyltransferase II; MAT-II
• Gene Name: MAT2A
• Related Disease: Familial thoracic aortic aneurysm and aortic dissection
• UniProt ID: METK2_HUMAN
• PDB ID: 2P02 ; 4KTT ; 4KTV ; 4NDN ; 5A19 ; 5A1G ; 5A1I ; 5UGH ; 6FAJ ; 6FBN ; 6FBO ; 6FBP ; 6FCB ; 6FCD ; 6FWB ; 6G6R ; 6P9V ; 6WKB ; 7BHR ; 7BHS ; 7BHT ; 7BHU ; 7BHV ; 7BHW ; 7BHX ; 7KCC ; 7KCE ; 7KCF ; 7KDA ; 7KDB ; 7L1A ; 7LNH ; 7RW5 ; 7RW7 ; 7RWG ; 7RWH ; 7RXV ; 7RXW ; 7RXX ; 8AXZ ; 8OOG ; 8P1T ; 8P1V ; 8P1W ; 8P4H
• EC Number: 2.5.1.6
• Pfam ID: PF02773 ; PF02772 ; PF00438
• Sequence:
  MNGQLNGFHEAFIEEGTFLFTSESVGEGHPDKICDQISDAVLDAHLQQDPDAKVACETVA
  KTGMILLAGEITSRAAVDYQKVVREAVKHIGYDDSSKGFDYKTCNVLVALEQQSPDIAQG
  VHLDRNEEDIGAGDQGLMFGYATDETEECMPLTIVLAHKLNAKLAELRRNGTLPWLRPDS
  KTQVTVQYMQDRGAVLPIRVHTIVISVQHDEEVCLDEMRDALKEKVIKAVVPAKYLDEDT
  IYHLQPSGRFVIGGPQGDAGLTGRKIIVDTYGGWGAHGGGAFSGKDYTKVDRSAAYAARW
  VAKSLVKGGLCRRVLVQVSYAIGVSHPLSISIFHYGTSQKSERELLEIVKKNFDLRPGVI
  VRDLDLKKPIYQRTAAYGHFGRDSFPWEVPKKLKY
• Function: Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate.
• Tissue Specificity: Detected in kidney.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS09847-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[2]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[23]

36 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 S-adenosylmethionine synthase isoform type-2 (MAT2A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[12]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[15]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[16]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[15]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[17]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[19]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[26]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[29]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[30]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[31]
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 S-adenosylmethionine synthase isoform type-2 (MAT2A).	[32]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of S-adenosylmethionine synthase isoform type-2 (MAT2A).	[33]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] Interplay between cellular methyl metabolism and adaptive efflux during oncogenic transformation from chronic arsenic exposure in human cells. J Biol Chem. 2008 Jul 11;283(28):19342-50.
• [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] Low-dose methotrexate inhibits methionine S-adenosyltransferase in vitro and in vivo. Mol Med. 2012 May 9;18:423-32.
• [13] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [14] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression. J Nutr Biochem. 2008 Jun;19(6):384-91.
• [17] In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer. Mol Cancer. 2006 Mar 28;5:13.
• [18] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [25] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [26] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [27] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [28] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [29] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [30] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [31] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [32] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [33] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.