dihydrofolate reductase

Target id: 2603

Nomenclature: dihydrofolate reductase

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

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for dihydrofolate reductase in GtoImmuPdb

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
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CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
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
PDB Id:  1KMV
Resolution:  1.05Å
Species:  Human
References:  3
Enzyme Reaction
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 Affinity Units 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]
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

References

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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

Nucleoside synthesis and metabolism: dihydrofolate reductase. Last modified on 22/10/2015. Accessed on 17/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2603.