Details of Drug Off-Target (DOT)

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

• DOT Name: Dihydrofolate reductase 2, mitochondrial (DHFR2)
• Synonyms: Dihydrofolate reductase, mitochondrial; EC 1.5.1.3; Dihydrofolate reductase-like protein 1
• Gene Name: DHFR2
• Related Disease: Meningioma
• UniProt ID: DYR2_HUMAN
• EC Number: 1.5.1.3
• Pfam ID: PF00186
• Sequence:
  MFLLLNCIVAVSQNMGIGKNGDLPRPPLRNEFRYFQRMTTTSSVEGKQNLVIMGRKTWFS
  IPEKNRPLKDRINLVLSRELKEPPQGAHFLARSLDDALKLTERPELANKVDMIWIVGGSS
  VYKEAMNHLGHLKLFVTRIMQDFESDTFFSEIDLEKYKLLPEYPGVLSDVQEGKHIKYKF
  EVCEKDD
• Function: Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Binds its own mRNA and that of DHFR.
• Tissue Specificity: Expressed in numerous cell lines.
• KEGG Pathway:
  One carbon pool by folate (hsa00670)
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Antifolate resistance (hsa01523)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)
• BioCyc Pathway: MetaCyc:ENSG00000178700-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
Meningioma	DISPT4TG	moderate	Genetic Variation	[1]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[2]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Dihydrofolate reductase 2, mitochondrial (DHFR2).	[6]

References

• [1] Polymorphisms of methionine metabolism and susceptibility to meningioma formation: laboratory investigation.J Neurosurg. 2008 May;108(5):999-1004. doi: 10.3171/JNS/2008/108/5/0999.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [11] 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.