Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3DVIGM)

• DOT Name: Dihydrofolate reductase (DHFR)
• Synonyms: EC 1.5.1.3
• Gene Name: DHFR
• Related Disease: Constitutional megaloblastic anemia with severe neurologic disease
• UniProt ID: DYR_HUMAN
• PDB ID: 1BOZ ; 1DHF ; 1DLR ; 1DLS ; 1DRF ; 1HFP ; 1HFQ ; 1HFR ; 1KMS ; 1KMV ; 1MVS ; 1MVT ; 1OHJ ; 1OHK ; 1PD8 ; 1PD9 ; 1PDB ; 1S3U ; 1S3V ; 1S3W ; 1U71 ; 1U72 ; 1YHO ; 2C2S ; 2C2T ; 2DHF ; 2W3A ; 2W3B ; 2W3M ; 3EIG ; 3F8Y ; 3F8Z ; 3F91 ; 3FS6 ; 3GHC ; 3GHV ; 3GHW ; 3GI2 ; 3GYF ; 3L3R ; 3N0H ; 3NTZ ; 3NU0 ; 3NXO ; 3NXR ; 3NXT ; 3NXV ; 3NXX ; 3NXY ; 3NZD ; 3OAF ; 3S3V ; 3S7A ; 4DDR ; 4G95 ; 4KAK ; 4KBN ; 4KD7 ; 4KEB ; 4KFJ ; 4M6J ; 4M6K ; 4M6L ; 4QHV ; 4QJC ; 5HPB ; 5HQY ; 5HQZ ; 5HSR ; 5HSU ; 5HT4 ; 5HT5 ; 5HUI ; 5HVB ; 5HVE ; 5SD6 ; 5SD7 ; 5SD8 ; 5SD9 ; 5SDA ; 5SDB ; 6A7C ; 6A7E ; 6DAV ; 6DE4 ; 6VCJ ; 7ESE ; 7XI7
• EC Number: 1.5.1.3
• Pfam ID: PF00186
• Sequence:
  MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
  IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
  VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
  EVYEKND
• Function: Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2.
• Tissue Specificity: Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain.
• 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)
  G1/S-Specific Transcription (R-HSA-69205)
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
• BioCyc Pathway: MetaCyc:HS09699-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
Constitutional megaloblastic anemia with severe neurologic disease	DIS9BHXU	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Dihydrofolate reductase (DHFR) decreases the response to substance of Methotrexate.	[35]
Chlorambucil	DMRKE63	Approved	Dihydrofolate reductase (DHFR) decreases the response to substance of Chlorambucil.	[36]
Floxuridine	DM04LR2	Approved	Dihydrofolate reductase (DHFR) affects the response to substance of Floxuridine.	[37]
Trimetrexate	DMDEA85	Approved	Dihydrofolate reductase (DHFR) decreases the response to substance of Trimetrexate.	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Dihydrofolate reductase (DHFR) decreases the abundance of Folic acid.	[1]

3 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 Dihydrofolate reductase (DHFR).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dihydrofolate reductase (DHFR).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Dihydrofolate reductase (DHFR).	[28]

41 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 Dihydrofolate reductase (DHFR).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dihydrofolate reductase (DHFR).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dihydrofolate reductase (DHFR).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dihydrofolate reductase (DHFR).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dihydrofolate reductase (DHFR).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dihydrofolate reductase (DHFR).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dihydrofolate reductase (DHFR).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Dihydrofolate reductase (DHFR).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dihydrofolate reductase (DHFR).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Dihydrofolate reductase (DHFR).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Dihydrofolate reductase (DHFR).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Dihydrofolate reductase (DHFR).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Dihydrofolate reductase (DHFR).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Dihydrofolate reductase (DHFR).	[17]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Dihydrofolate reductase (DHFR).	[18]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Dihydrofolate reductase (DHFR).	[19]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Dihydrofolate reductase (DHFR).	[12]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Dihydrofolate reductase (DHFR).	[20]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Dihydrofolate reductase (DHFR).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Dihydrofolate reductase (DHFR).	[22]
Tubocurarine	DMBZIVP	Approved	Tubocurarine decreases the expression of Dihydrofolate reductase (DHFR).	[20]
Levofloxacin	DMS60RB	Approved	Levofloxacin decreases the activity of Dihydrofolate reductase (DHFR).	[23]
Mecamylamine	DMGQFYB	Approved	Mecamylamine decreases the expression of Dihydrofolate reductase (DHFR).	[20]
Ceftazidime	DM41GRA	Approved	Ceftazidime decreases the activity of Dihydrofolate reductase (DHFR).	[23]
Cefepime	DMHVWIK	Approved	Cefepime decreases the activity of Dihydrofolate reductase (DHFR).	[23]
Ceftriaxone	DMCEW64	Approved	Ceftriaxone decreases the activity of Dihydrofolate reductase (DHFR).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dihydrofolate reductase (DHFR).	[24]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Dihydrofolate reductase (DHFR).	[25]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Dihydrofolate reductase (DHFR).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dihydrofolate reductase (DHFR).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dihydrofolate reductase (DHFR).	[29]
Ferulic Acid	DMJC7NF	Patented	Ferulic Acid decreases the activity of Dihydrofolate reductase (DHFR).	[23]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Dihydrofolate reductase (DHFR).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dihydrofolate reductase (DHFR).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dihydrofolate reductase (DHFR).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Dihydrofolate reductase (DHFR).	[8]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Dihydrofolate reductase (DHFR).	[32]
Syringic Acid	DM802V7	Investigative	Syringic Acid decreases the activity of Dihydrofolate reductase (DHFR).	[23]
Naringin	DM4DG1Y	Investigative	Naringin decreases the activity of Dihydrofolate reductase (DHFR).	[23]
[3H]folinic acid	DME0XHN	Investigative	[3H]folinic acid increases the expression of Dihydrofolate reductase (DHFR).	[33]
Distamycin A	DMPVNDK	Investigative	Distamycin A decreases the expression of Dihydrofolate reductase (DHFR).	[34]

References

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• [22] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
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