Dihydrofolate reductase

UniProt P00374 Organism Homo sapiens Gene DHFR EC 1.5.1.3

Also known as: DHFR

Function

Catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate in a NADPH-dependent manner. Key enzyme in folate metabolism. Contributes to the nuclear and mitochondrial de novo 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.

Classification

Family (Pfam): PF00186 DHFR_1
InterPro: DHFR, DHFR-like_dom_sf, DHFR_CS, DHFR_dom
Functional cluster: Nucleotide & Amino-Acid Biosynthesis Enzymes

Experimental structures · PDB · 89

1BOZ X-ray 2.10A
1DHF X-ray 2.30A
1DLR X-ray 2.30A
1DLS X-ray 2.30A
1DRF X-ray 2.00A
1HFP X-ray 2.10A
1HFQ X-ray 2.10A
1HFR X-ray 2.10A
1KMS X-ray 1.09A
1KMV X-ray 1.05A
1MVS X-ray 1.90A
1MVT X-ray 1.80A
… and 77 more

A predicted model is available from AlphaFold.

Gene Ontology · 23

Disease associations

constitutional megaloblastic anemia with severe neurologic disease MONDO:0013456

Drugs targeting this protein · 9

Related proteins · sequence + function similarity

Dihydrofolate reductase 0.97
Dihydrofolate reductase 0.97
Dihydrofolate reductase 0.97
Dihydrofolate reductase 0.97
Dihydrofolate reductase 0.96
Dihydrofolate reductase 2, mitochondrial 0.95
Dihydrofolate reductase 0.94
Viral dihydrofolate reductase 0.93
Viral dihydrofolate reductase 0.83
Viral dihydrofolate reductase 0.78
Dihydrofolate reductase 0.76
Dihydrofolate reductase 0.74

Co-cited proteins · studied together in the literature

Dihydrofolate reductase 2, mitochondrial 2 shared papers
Dihydrofolate reductase 1 shared papers
Thymidylate synthase 3 shared papers
Dihydrofolate reductase 1 shared papers
Serine hydroxymethyltransferase, cytosolic 1 shared papers
Serine hydroxymethyltransferase, mitochondrial 1 shared papers
SUMO-conjugating enzyme UBC9 1 shared papers

Literature · 29 cited papers

Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis. J. Biol. Chem. · 2012
Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc. Natl. Acad. Sci. U.S.A. · 2011
The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional. Proc. Natl. Acad. Sci. U.S.A. · 2011
Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am. J. Hum. Genet. · 2011
Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am. J. Hum. Genet. · 2011
Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents. J. Med. Chem. · 2009
Multiple conformers in active site of human dihydrofolate reductase F31R/Q35E double mutant suggest structural basis for methotrexate resistance. J. Biol. Chem. · 2009
Correlations of inhibitor kinetics for Pneumocystis jirovecii and human dihydrofolate reductase with structural data for human active site mutant enzyme complexes. Biochemistry · 2009
Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase. Clin. Chem. Lab. Med. · 2007
Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation. J. Med. Chem. · 2007
Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH. J. Biomol. NMR · 2005
… and 17 more in the literature graph

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