Details of Drug Off-Target (DOT)

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

• DOT Name: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L)
• Synonyms: NADP-dependent methylenetetrahydrofolate dehydrogenase 2-like protein; MTHFD2-like
• Gene Name: MTHFD2L
• Related Disease: Advanced cancer
• UniProt ID: MTD2L_HUMAN
• PDB ID: 7QEI
• EC Number: 1.5.1.15; 1.5.1.5; 3.5.4.9
• Pfam ID: PF00763 ; PF02882
• Sequence:
  MTVPVRGFSLLRGRLGRAPALGRSTAPSVRAPGEPGSAFRGFRSSGVRHEAIIISGTEMA
  KHIQKEIQRGVESWVSLGNRRPHLSIILVGDNPASHTYVRNKIRAASAVGICSELILKPK
  DVSQEELLDVTDQLNMDPRVSGILVQLPLPDHVDERTICNGIAPEKDVDGFHIINIGRLC
  LDQHSLIPATASAVWEIIKRTGIQTFGKNVVVAGRSKNVGMPIAMLLHTDGEHERPGGDA
  TVTIAHRYTPKEQLKIHTQLADIIIVAAGIPKLITSDMVKEGAAVIDVGINYVHDPVTGK
  TKLVGDVDFEAVKKKAGFITPVPGGVGPMTVAMLLKNTLLAAKKIIY
• Function: Bifunctional mitochondrial folate-interconverting enzyme that has both NAD/NADP-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities.
• Tissue Specificity: Isoform 1, isoform 4 and isoform 5 are expressed in brain and placenta.
• KEGG Pathway:
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]

1 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 Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial (MTHFD2L).	[9]

References

• [1] Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer.Gene. 2019 Oct 20;716:144032. doi: 10.1016/j.gene.2019.144032. Epub 2019 Aug 1.
• [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] 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] 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] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] 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.
• [11] 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.