Details of Drug Off-Target (DOT)

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

• DOT Name: C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1)
• Synonyms: C1-THF synthase; Epididymis secretory sperm binding protein
• Gene Name: MTHFD1
• Related Disease:
  Childhood acute lymphoblastic leukemia
  Small-cell lung cancer
  Acute lymphocytic leukaemia
  Alzheimer disease
  Autism
  B-cell neoplasm
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Chronic obstructive pulmonary disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
  Depression
  Epilepsy
  Esophageal cancer
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  High blood pressure
  Lung cancer
  Lung carcinoma
  Megaloblastic anemia
  Migraine disorder
  Myocardial infarction
  Neoplasm of esophagus
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Obesity
  Severe combined immunodeficiency
  Clear cell renal carcinoma
  Schizophrenia
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Acute myocardial infarction
  Advanced cancer
  Parkinson disease
• UniProt ID: C1TC_HUMAN
• PDB ID: 1A4I; 1DIA; 1DIB; 1DIG; 6ECP; 6ECQ; 6ECR
• EC Number: 1.5.1.5; 3.5.4.9; 6.3.4.3
• Pfam ID: PF01268 ; PF00763 ; PF02882
• Sequence:
  MAPAEILNGKEISAQIRARLKNQVTQLKEQVPGFTPRLAILQVGNRDDSNLYINVKLKAA
  EEIGIKATHIKLPRTTTESEVMKYITSLNEDSTVHGFLVQLPLDSENSINTEEVINAIAP
  EKDVDGLTSINAGKLARGDLNDCFIPCTPKGCLELIKETGVPIAGRHAVVVGRSKIVGAP
  MHDLLLWNNATVTTCHSKTAHLDEEVNKGDILVVATGQPEMVKGEWIKPGAIVIDCGINY
  VPDDKKPNGRKVVGDVAYDEAKERASFITPVPGGVGPMTVAMLMQSTVESAKRFLEKFKP
  GKWMIQYNNLNLKTPVPSDIDISRSCKPKPIGKLAREIGLLSEEVELYGETKAKVLLSAL
  ERLKHRPDGKYVVVTGITPTPLGEGKSTTTIGLVQALGAHLYQNVFACVRQPSQGPTFGI
  KGGAAGGGYSQVIPMEEFNLHLTGDIHAITAANNLVAAAIDARIFHELTQTDKALFNRLV
  PSVNGVRRFSDIQIRRLKRLGIEKTDPTTLTDEEINRFARLDIDPETITWQRVLDTNDRF
  LRKITIGQAPTEKGHTRTAQFDISVASEIMAVLALTTSLEDMRERLGKMVVASSKKGEPV
  SAEDLGVSGALTVLMKDAIKPNLMQTLEGTPVFVHAGPFANIAHGNSSIIADRIALKLVG
  PEGFVVTEAGFGADIGMEKFFNIKCRYSGLCPHVVVLVATVRALKMHGGGPTVTAGLPLP
  KAYIQENLELVEKGFSNLKKQIENARMFGIPVVVAVNAFKTDTESELDLISRLSREHGAF
  DAVKCTHWAEGGKGALALAQAVQRAAQAPSSFQLLYDLKLPVEDKIRIIAQKIYGADDIE
  LLPEAQHKAEVYTKQGFGNLPICMAKTHLSLSHNPEQKGVPTGFILPIRDIRASVGAGFL
  YPLVGTMSTMPGLPTRPCFYDIDLDPETEQVNGLF
• Function: Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate. These derivatives of tetrahydrofolate are differentially required in nucleotide and amino acid biosynthesis, (6S)-10-formyltetrahydrofolate being required for purine biosynthesis while (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate is used for serine and methionine biosynthesis for instance.
• Tissue Specificity: Ubiquitous.
• 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)
• BioCyc Pathway: MetaCyc:HS02138-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood acute lymphoblastic leukemia	DISJ5D6U	Definitive	Genetic Variation	[1]
Small-cell lung cancer	DISK3LZD	Definitive	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[7]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[8]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[9]
Colon cancer	DISVC52G	Strong	Genetic Variation	[10]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[11]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[12]
Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia	DIST6ZI1	Strong	Autosomal recessive	[13]
Depression	DIS3XJ69	Strong	Biomarker	[14]
Epilepsy	DISBB28L	Strong	Genetic Variation	[15]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[17]
High blood pressure	DISY2OHH	Strong	Posttranslational Modification	[18]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Megaloblastic anemia	DISVIZPC	Strong	Biomarker	[19]
Migraine disorder	DISFCQTG	Strong	Genetic Variation	[20]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[21]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[22]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Genetic Variation	[23]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Biomarker	[19]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[24]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[4]
Epithelial ovarian cancer	DIS56MH2	Disputed	Genetic Variation	[25]
Ovarian cancer	DISZJHAP	Disputed	Genetic Variation	[25]
Ovarian neoplasm	DISEAFTY	Disputed	Genetic Variation	[25]
Acute myocardial infarction	DISE3HTG	Limited	Genetic Variation	[21]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[26]
Parkinson disease	DISQVHKL	Limited	Biomarker	[27]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1) affects the response to substance of Methotrexate.	[52]
Floxuridine	DM04LR2	Approved	C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1) affects the response to substance of Floxuridine.	[53]
Choline	DM5D9YK	Investigative	C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1) affects the response to substance of Choline.	[54]

23 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 C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[34]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[36]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[38]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[39]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[34]
Menadione	DMSJDTY	Approved	Menadione affects the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[40]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[41]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[42]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[43]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[46]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[47]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[49]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[50]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[51]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of C-1-tetrahydrofolate synthase, cytoplasmic (MTHFD1).	[48]

References

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