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dihydrofolate reductase

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2603

Nomenclature: dihydrofolate reductase

Abbreviated Name: DHFR

Family: 1.-.-.- Oxidoreductases, Nucleoside synthesis and metabolism

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 187 5q14.1 DHFR dihydrofolate reductase
Mouse - 187 13 47.64 cM Dhfr dihydrofolate reductase
Rat - 187 2q12 Dhfr dihydrofolate reductase
Database Links Click here for help
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CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
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RefSeq Nucleotide
RefSeq Protein
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Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Human dihydrofolate reductase complexed with NADPH and (Z)-6-(2-[2,5-dimethoxyphenyl]ethen-1-YL)-2,4-diamino-5-methylpyrido[2,3-D]pyrimidine (SRI-9662), a lipophilic antifolate
PDB Id:  1KMV
Resolution:  1.05Å
Species:  Human
References:  4
Enzyme Reaction Click here for help
EC Number: 1.5.1.3

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 9 [PMID: 15615544] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 10.5 pKi 5
pKi 10.5 (Ki 3.4x10-11 M) [5]
methotrexate Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.9 pKi 6
pKi 8.9 (Ki 1.2x10-9 M) [6]
pemetrexed Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.1 pKi 2,7
pKi 8.1 (Ki 7x10-9 M) [2,7]
trimetrexate Small molecule or natural product Approved drug Hs Inhibition 7.9 pKi 6
pKi 7.9 (Ki 1.3x10-8 M) [6]
Description: In vitro inhibition of wild-type human DHFR
pralatrexate Small molecule or natural product Approved drug Primary target of this compound Hs Inhibition 7.3 pKi 3
pKi 7.3 (Ki 4.5x10-8 M) [3]
iclaprim Small molecule or natural product Hs Inhibition 6.1 pKi
pKi 6.1 (Ki 7.75x10-7 M)
diflunisal Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 4.5 pKi 1
pKi 4.5 (Ki 3.4x10-5 M) This is well below the peak plasma diflunisal levels reached at typical clinically administered doses. [1]
Immunopharmacology Comments
The anti-folate drug methotrexate, is an effective disease-modifying anti-rheumatic drugs (DMARDs) that is used in the treatment of rheumatoid arthritis and other diseases associated with chronic inflammation. Its mechanism is thought to be inhibition of folate pathway enzymes, primarily DHFR.

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) that contain carboxylate groups has been reported to competitively inhibit DHFR [1]. NMR and X-ray crystallographic analysis was used to reveal the binding mode of these NSAIDs. They were discovered to bind to the region of the enzyme's substrate binding domain that interacts with the p-aminobenzoyl-l-glutamate (pABG) moiety of folate. This information raises the potential that these compounds or optimised analogues could disrupt the inflammatory process via a mechanism in co-operation with cyclooxygenase inhibition.
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Megaloblastic anemia due to dihydrofolate reductase deficiency
Synonyms: Constitutional megaloblastic anemia with severe neurologic disease [Orphanet: ORPHA319651]
OMIM: 613839
Orphanet: ORPHA319651

References

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1. Duff MR Jr, Gabel SA, Pedersen LC, DeRose EF, Krahn JM, Howell EE, London RE. (2020) The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase. Journal of Medicinal Chemistry, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.0c00546

2. Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL. (2005) Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. J Med Chem, 48 (16): 5329-36. [PMID:16078850]

3. Izbicka E, Diaz A, Streeper R, Wick M, Campos D, Steffen R, Saunders M. (2009) Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. Cancer Chemother Pharmacol, 64 (5): 993-9. [PMID:19221750]

4. Klon AE, Héroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW. (2002) Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol, 320 (3): 677-93. [PMID:12096917]

5. Rosowsky A, Forsch RA, Wright JE. (2004) Synthesis and in vitro antifolate activity of rotationally restricted aminopterin and methotrexate analogues. J Med Chem, 47 (27): 6958-63. [PMID:15615544]

6. Rosowsky A, Mota CE, Queener SF, Waltham M, Ercikan-Abali E, Bertino JR. (1995) 2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii. J Med Chem, 38 (5): 745-52. [PMID:7877140]

7. Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM. (1998) Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul, 38: 135-52. [PMID:9762351]

How to cite this page

1.-.-.- Oxidoreductases: dihydrofolate reductase. Last modified on 04/08/2020. Accessed on 15/06/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2603.