dihydrofolate reductase | 1.-.-.- Oxidoreductases | IUPHAR/BPS Guide to PHARMACOLOGY

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dihydrofolate reductase

Target not currently curated 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 5q11.2-q13.2 DHFR dihydrofolate reductase
Mouse - 187 13 C3 Dhfr dihydrofolate reductase
Rat - 187 2q12 Dhfr dihydrofolate reductase
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures
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
Resolution:  1.05Å
Species:  Human
References:  3
Enzyme Reaction
EC Number:

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 9 [PMID: 15615544] Hs Inhibition 10.5 pKi 4
pKi 10.5 (Ki 3.4x10-11 M) [4]
methotrexate Hs Inhibition 8.9 pKi 5
pKi 8.9 (Ki 1.2x10-9 M) [5]
pemetrexed Hs Inhibition 8.1 pKi 1,6
pKi 8.1 (Ki 7x10-9 M) [1,6]
trimetrexate Hs Inhibition 7.9 pKi 5
pKi 7.9 (Ki 1.3x10-8 M) [5]
Description: In vitro inhibition of wild-type human DHFR
pralatrexate Hs Inhibition 7.3 pKi 2
pKi 7.3 (Ki 4.5x10-8 M) [2]
iclaprim Hs Inhibition 6.1 pKi
pKi 6.1 (Ki 7.75x10-7 M)
Clinically-Relevant Mutations and Pathophysiology
Disease:  Megaloblastic anemia due to dihydrofolate reductase deficiency
Synonyms: Constitutional megaloblastic anemia with severe neurologic disease [Orphanet: ORPHA319651]
OMIM: 613839
Orphanet: ORPHA319651


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1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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 06/05/2020. Accessed on 19/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2603.