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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 | ||||||
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 | |
Alphafold | P00374 (Hs), P00375 (Mm), Q920D2 (Rn) |
BRENDA | 1.5.1.3 |
CATH/Gene3D | 3.40.430.10 |
ChEMBL Target | CHEMBL202 (Hs), CHEMBL4564 (Mm), CHEMBL2363 (Rn) |
DrugBank Target | P00374 (Hs) |
Ensembl Gene | ENSG00000228716 (Hs), ENSMUSG00000021707 (Mm), ENSRNOG00000013521 (Rn) |
Entrez Gene | 1719 (Hs), 13361 (Mm), 24312 (Rn) |
Human Protein Atlas | ENSG00000228716 (Hs) |
KEGG Enzyme | 1.5.1.3 |
KEGG Gene | hsa:1719 (Hs), mmu:13361 (Mm), rno:24312 (Rn) |
OMIM | 126060 (Hs) |
Orphanet | ORPHA159526 (Hs) |
Pharos | P00374 (Hs) |
RefSeq Nucleotide | NM_000791 (Hs), NM_010049 (Mm), NM_130400 (Rn) |
RefSeq Protein | NP_000782 (Hs), NP_034179 (Mm), NP_569084 (Rn) |
SynPHARM | 79522 (in complex with methotrexate) |
UniProtKB | P00374 (Hs), P00375 (Mm), Q920D2 (Rn) |
Wikipedia | DHFR (Hs) |
Selected 3D Structures | |||||||||||
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Enzyme Reaction | ||||
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Download all structure-activity data for this target as a CSV file
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | ||||||||||||
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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]
1.-.-.- Oxidoreductases: dihydrofolate reductase. Last modified on 04/08/2020. Accessed on 08/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2603.