Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK72E4F)

• DOT Name: S-adenosylmethionine synthase isoform type-1 (MAT1A)
• Synonyms: AdoMet synthase 1; EC 2.5.1.6; Methionine adenosyltransferase 1; MAT 1; Methionine adenosyltransferase I/III; MAT-I/III
• Gene Name: MAT1A
• Related Disease: Methionine adenosyltransferase deficiency
• UniProt ID: METK1_HUMAN
• PDB ID: 2OBV; 6SW5; 6SW6; 8SWA
• EC Number: 2.5.1.6
• Pfam ID: PF02773 ; PF02772 ; PF00438
• Sequence:
  MNGPVDGLCDHSLSEGVFMFTSESVGEGHPDKICDQISDAVLDAHLKQDPNAKVACETVC
  KTGMVLLCGEITSMAMVDYQRVVRDTIKHIGYDDSAKGFDFKTCNVLVALEQQSPDIAQC
  VHLDRNEEDVGAGDQGLMFGYATDETEECMPLTIILAHKLNARMADLRRSGLLPWLRPDS
  KTQVTVQYMQDNGAVIPVRIHTIVISVQHNEDITLEEMRRALKEQVIRAVVPAKYLDEDT
  VYHLQPSGRFVIGGPQGDAGVTGRKIIVDTYGGWGAHGGGAFSGKDYTKVDRSAAYAARW
  VAKSLVKAGLCRRVLVQVSYAIGVAEPLSISIFTYGTSQKTERELLDVVHKNFDLRPGVI
  VRDLDLKKPIYQKTACYGHFGRSEFPWEVPRKLVF
• 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: Expressed in liver.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  Sulfur amino acid metabolism (R-HSA-1614635)
  Metabolism of ingested SeMet, Sec, MeSec into H2Se (R-HSA-2408508)
  Defective MAT1A causes MATD (R-HSA-5579024)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS07715-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
Methionine adenosyltransferase deficiency	DIS4SI69	Definitive	Autosomal recessive	[1]

7 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-1 (MAT1A).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[6]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[8]

3 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 S-adenosylmethionine synthase isoform type-1 (MAT1A).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of S-adenosylmethionine synthase isoform type-1 (MAT1A).	[10]

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] 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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [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] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.