Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ39JNR)

• DOT Name: 5-formyltetrahydrofolate cyclo-ligase (MTHFS)
• Synonyms: EC 6.3.3.2; 5,10-methenyl-tetrahydrofolate synthetase; MTHFS; Methenyl-THF synthetase
• Gene Name: MTHFS
• Related Disease:
  Chronic kidney disease
  Lung cancer
  Lung carcinoma
  Nephropathy
  Non-small-cell lung cancer
  Small-cell lung cancer
  Diabetic kidney disease
  Isolated cleft lip
  Isolated cleft palate
  Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination
  Isolated congenital microcephaly
  Mycoplasma pneumoniae pneumonia
• UniProt ID: MTHFS_HUMAN
• PDB ID: 3HXT; 3HY3; 3HY4; 3HY6
• EC Number: 6.3.3.2
• Pfam ID: PF01812
• Sequence:
  MAAAAVSSAKRSLRGELKQRLRAMSAEERLRQSRVLSQKVIAHSEYQKSKRISIFLSMQD
  EIETEEIIKDIFQRGKICFIPRYRFQSNHMDMVRIESPEEISLLPKTSWNIPQPGEGDVR
  EEALSTGGLDLIFMPGLGFDKHGNRLGRGKGYYDAYLKRCLQHQEVKPYTLALAFKEQIC
  LQVPVNENDMKVDEVLYEDSSTA
• Function: Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids. Catalyzes the irreversible conversion of 5-formyltetrahydrofolate (5-FTHF) to yield 5,10-methenyltetrahydrofolate.
• KEGG Pathway:
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Lung cancer	DISCM4YA	Definitive	Genetic Variation	[2]
Lung carcinoma	DISTR26C	Definitive	Genetic Variation	[2]
Nephropathy	DISXWP4P	Definitive	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[2]
Small-cell lung cancer	DISK3LZD	Definitive	Biomarker	[2]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[3]
Isolated cleft lip	DIS2O2JV	Strong	Biomarker	[4]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[4]
Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination	DISTL979	Strong	Autosomal recessive	[5]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[5]
Mycoplasma pneumoniae pneumonia	DIS1AW2Z	moderate	Biomarker	[6]

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 5-formyltetrahydrofolate cyclo-ligase (MTHFS).	[7]

6 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 5-formyltetrahydrofolate cyclo-ligase (MTHFS).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 5-formyltetrahydrofolate cyclo-ligase (MTHFS).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 5-formyltetrahydrofolate cyclo-ligase (MTHFS).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of 5-formyltetrahydrofolate cyclo-ligase (MTHFS).	[11]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of 5-formyltetrahydrofolate cyclo-ligase (MTHFS).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of 5-formyltetrahydrofolate cyclo-ligase (MTHFS).	[13]

References

• [1] Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies.BMC Med Genet. 2008 Jun 3;9:49. doi: 10.1186/1471-2350-9-49.
• [2] Prognostic significance of folate metabolism polymorphisms for lung cancer.Br J Cancer. 2007 Jul 16;97(2):247-52. doi: 10.1038/sj.bjc.6603830. Epub 2007 May 29.
• [3] The impact of 5,10-methenyltetrahydrofolate synthetase polymorphism on diabetic nephropathy in the Taiwanese population.Genet Test Mol Biomarkers. 2012 Feb;16(2):142-5. doi: 10.1089/gtmb.2011.0050. Epub 2011 Sep 6.
• [4] Folate pathway and nonsyndromic cleft lip and palate.Birth Defects Res A Clin Mol Teratol. 2011 Jan;91(1):50-60. doi: 10.1002/bdra.20740. Epub 2010 Dec 1.
• [5] 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metab. 2018 Sep;125(1-2):118-126. doi: 10.1016/j.ymgme.2018.06.006. Epub 2018 Jun 15.
• [6] Investigations of Amino Acids in the 5-Formyltetrahydrofolate Binding Site of 5,10-Methenyltetrahydrofolate Synthetase from Mycoplasma pneumonia.Protein J. 2019 Aug;38(4):409-418. doi: 10.1007/s10930-019-09861-4.
• [7] 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.
• [8] 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.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [13] 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.