Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUBJSR7)

• DOT Name: Methylenetetrahydrofolate reductase (MTHFR)
• Synonyms: NADPH; EC 1.5.1.53
• Gene Name: MTHFR
• Related Disease: Homocystinuria due to methylene tetrahydrofolate reductase deficiency
• UniProt ID: MTHR_HUMAN
• PDB ID: 6FCX; 8QA4; 8QA5; 8QA6
• EC Number: 1.5.1.53
• Pfam ID: PF02219
• Sequence:
  MVNEARGNSSLNPCLEGSASSGSESSKDSSRCSTPGLDPERHERLREKMRRRLESGDKWF
  SLEFFPPRTAEGAVNLISRFDRMAAGGPLYIDVTWHPAGDPGSDKETSSMMIASTAVNYC
  GLETILHMTCCRQRLEEITGHLHKAKQLGLKNIMALRGDPIGDQWEEEEGGFNYAVDLVK
  HIRSEFGDYFDICVAGYPKGHPEAGSFEADLKHLKEKVSAGADFIITQLFFEADTFFRFV
  KACTDMGITCPIVPGIFPIQGYHSLRQLVKLSKLEVPQEIKDVIEPIKDNDAAIRNYGIE
  LAVSLCQELLASGLVPGLHFYTLNREMATTEVLKRLGMWTEDPRRPLPWALSAHPKRREE
  DVRPIFWASRPKSYIYRTQEWDEFPNGRWGNSSSPAFGELKDYYLFYLKSKSPKEELLKM
  WGEELTSEESVFEVFVLYLSGEPNRNGHKVTCLPWNDEPLAAETSLLKEELLRVNRQGIL
  TINSQPNINGKPSSDPIVGWGPSGGYVFQKAYLEFFTSRETAEALLQVLKKYELRVNYHL
  VNVKGENITNAPELQPNAVTWGIFPGREIIQPTVVDPVSFMFWKDEAFALWIERWGKLYE
  EESPSRTIIQYIHDNYFLVNLVDNDFPLDNCLWQVVEDTLELLNRPTQNARETEAP
• Function: Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Represents a key regulatory connection between the folate and methionine cycles (Probable).
• KEGG Pathway:
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
  Antifolate resistance (hsa01523)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)
• BioCyc Pathway: MetaCyc:HS11117-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
Homocystinuria due to methylene tetrahydrofolate reductase deficiency	DISYSIA1	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 11 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Methylenetetrahydrofolate reductase (MTHFR) increases the response to substance of Arsenic.	[14]
Fluorouracil	DMUM7HZ	Approved	Methylenetetrahydrofolate reductase (MTHFR) increases the response to substance of Fluorouracil.	[15]
Panobinostat	DM58WKG	Approved	Methylenetetrahydrofolate reductase (MTHFR) increases the Platelet aggregation ADR of Panobinostat.	[16]
Cytarabine	DMZD5QR	Approved	Methylenetetrahydrofolate reductase (MTHFR) affects the response to substance of Cytarabine.	[18]
Clozapine	DMFC71L	Approved	Methylenetetrahydrofolate reductase (MTHFR) affects the response to substance of Clozapine.	[19]
Olanzapine	DMPFN6Y	Approved	Methylenetetrahydrofolate reductase (MTHFR) affects the response to substance of Olanzapine.	[19]
Sulfasalazine	DMICA9H	Approved	Methylenetetrahydrofolate reductase (MTHFR) increases the response to substance of Sulfasalazine.	[20]
Floxuridine	DM04LR2	Approved	Methylenetetrahydrofolate reductase (MTHFR) affects the response to substance of Floxuridine.	[21]
Benazepril	DMH1M9B	Approved	Methylenetetrahydrofolate reductase (MTHFR) affects the response to substance of Benazepril.	[22]
Riboflavin	DM8YMWE	Approved	Methylenetetrahydrofolate reductase (MTHFR) affects the response to substance of Riboflavin.	[23]
Methotrexate	DM2TEOL	Phase 1/2 Trial	Methylenetetrahydrofolate reductase (MTHFR) increases the Dose-limiting toxicity ADR of Methotrexate.	[24]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Methylenetetrahydrofolate reductase (MTHFR) decreases the abundance of Folic acid.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Methylenetetrahydrofolate reductase (MTHFR).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Methylenetetrahydrofolate reductase (MTHFR).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[6]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[7]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Methylenetetrahydrofolate reductase (MTHFR).	[13]

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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Homocysteine modulates the effect of simvastatin on expression of ApoA-I and NF-kappaB/iNOS. Cardiovasc Res. 2008 Oct 1;80(1):151-8.
• [8] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [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] BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget. 2013 Nov;4(11):2080-95.
• [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.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [14] Genetic variation in glutathione S-transferase omega-1, arsenic methyltransferase and methylene-tetrahydrofolate reductase, arsenic exposure and bladder cancer: a case-control study. Environ Health. 2012 Jun 29;11:43. doi: 10.1186/1476-069X-11-43.
• [15] Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol. 2005 Mar 1;23(7):1365-9. doi: 10.1200/JCO.2005.06.219.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [17] Functional inference of the methylenetetrahydrofolate reductase 677C > T and 1298A > C polymorphisms from a large-scale epidemiological study. Hum Genet. 2007 Mar;121(1):57-64. doi: 10.1007/s00439-006-0290-2. Epub 2006 Nov 18.
• [18] DNA methylation and sensitivity to antimetabolites in cancer cell lines. Oncol Rep. 2008 Feb;19(2):407-12.
• [19] MTHFR and risk of metabolic syndrome in patients with schizophrenia. Schizophr Res. 2010 Aug;121(1-3):193-8. doi: 10.1016/j.schres.2010.05.030. Epub 2010 Jun 12.
• [20] The effect of 677C>T and 1298A>C MTHFR polymorphisms on sulfasalazine treatment outcome in rheumatoid arthritis. Braz J Med Biol Res. 2009 Jul;42(7):660-4. doi: 10.1590/s0100-879x2009000700011.
• [21] Folic Acid-Metabolizing Enzymes Regulate the Antitumor Effect of 5-Fluoro-2'-Deoxyuridine in Colorectal Cancer Cell Lines. PLoS One. 2016 Sep 29;11(9):e0163961. doi: 10.1371/journal.pone.0163961. eCollection 2016.
• [22] A common haplotype on methylenetetrahydrofolate reductase gene modifies the effect of angiotensin-converting enzyme inhibitor on blood pressure in essential hypertension patients--a family-based association study. Clin Exp Hypertens. 2005 Aug;27(6):509-21.
• [23] Protective association of MTHFR polymorphism on cervical intraepithelial neoplasia is modified by riboflavin status. Nutrition. 2007 Mar;23(3):229-35. doi: 10.1016/j.nut.2006.12.006. Epub 2007 Feb 14.
• [24] Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival. Haematologica. 2007 Apr;92(4):478-85. doi: 10.3324/haematol.10587.