D
IPR001796

Dihydrofolate reductase domain

InterPro entry
Short nameDHFR_dom
Overlapping
homologous
superfamilies
 

Description

Dihydrofolate reductase (DHFR) (
1.5.1.3
) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, which can be used inde novosynthesis both certain amino acids, purines and deoxythymidine phosphate (the precursors of DNA synthesis)
[1]
, and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood
[2]
.

Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar
[3]
. The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown
[4]
to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself
[5]
.

References

1.A gene for dihydrofolate reductase in a herpesvirus. Trimble JJ, Murthy SC, Bakker A, Grassmann R, Desrosiers RC. Science 239, 1145-7, (1988). View articlePMID: 2830673

2.Crystal structure of human dihydrofolate reductase complexed with folate. Oefner C, D'Arcy A, Winkler FK. Eur. J. Biochem. 174, 377-85, (1988). View articlePMID: 3383852

3.Porcine liver dihydrofolate reductase. Purification, properties, and amino acid sequence. Smith SL, Patrick P, Stone D, Phillips AW, Burchall JJ. J. Biol. Chem. 254, 11475-84, (1979). View articlePMID: 500653

4.Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate. Bolin JT, Filman DJ, Matthews DA, Hamlin RC, Kraut J. J. Biol. Chem. 257, 13650-62, (1982). View articlePMID: 6815178

5.Antifolate drug selection results in duplication and rearrangement of chromosome 7 in Plasmodium chabaudi. Cowman AF, Lew AM. Mol. Cell. Biol. 9, 5182-8, (1989). View articlePMID: 2601715

GO terms

Cross References

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