PROSITE documentation PDOC00072

Dihydrofolate reductase (DHFR) domain signature and profile




Description

Dihydrofolate reductases (DHFRs) (EC 1.5.1.3) [1] are ubiquitous enzymes which catalyze the NADPH-linked reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. DHFRs are also capable of catalyzing the NADPH-linked reduction of folate to 7,8-dihydrofolate, but at a lesser rate, which varies among species. They can be inhibited by a number of antagonists such as trimethroprim and methotrexate which are used as antibacterial or anticancerous agents.

Thymidylate synthase (TS) (see <PDOC00086>) and DHFR catalyze sequential reactions in the thymidylate cycle, which supplies cells with their sole de novo source of 2'-deoxythymidylate (dTMP) for DNA synthesis. TS catalyzes a reductive methylation of 2'deoxyuridylate (dUMP) to form dTMP in which the cofactor for the reaction, 5,10-methylenetetrahydrofolate is converted to dihydrofolate (FH(2)). DHFR then reduces FH(2) to tetrahydrofolate (FH(4)) in a reaction requiring NADPH. In sources as diverse as bacteriophage, prokaryotes, fungi, mammalian viruses, and vertebrates, TS and DHFR are distinct monofunctional enzymes. Protozoa and at least some plants are unusual in having a joined bifunctional polypetide that catalyzes both reactions [2,3].

An eight-stranded β sheet consisting of seven parallel strands and a carboxy-terminal antiparallel strand composes the core of the DHFR domain. The β-sheet core is flanked by α-helices (see <PDB:1DRH>) [2,3,4,5,6].

We have derived a signature pattern from a region in the N-terminal part of the DHFR domain, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown [7] to be involved in the binding of substrate by the enzyme. We have also developed a profile, which covers the entire DHFR domain.

Last update:

September 2007 / Text revised; profile added.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

DHFR_2, PS51330; Dihydrofolate reductase (DHFR) domain profile  (MATRIX)

DHFR_1, PS00075; Dihydrofolate reductase (DHFR) domain signature  (PATTERN)


References

1SourceHarpers' Review of Biochemistry, Lange, Los Altos (1985).

2AuthorsKnighton D.R., Kan C.-C., Howland E., Janson C.A., Hostomska Z., Welsh K.M., Matthews D.A.
TitleStructure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase.
SourceNat. Struct. Biol. 1:186-194(1994).
PubMed ID7656037

3AuthorsYuvaniyama J., Chitnumsub P., Kamchonwongpaisan S., Vanichtanankul J., Sirawaraporn W., Taylor P., Walkinshaw M.D., Yuthavong Y.
TitleInsights into antifolate resistance from malarial DHFR-TS structures.
SourceNat. Struct. Biol. 10:357-365(2003).
PubMed ID12704428
DOI10.1038/nsb921

4AuthorsDavies J.F. II, Delcamp T.J., Prendergast N.J., Ashford V.A., Freisheim J.H., Kraut J.
TitleCrystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate.
SourceBiochemistry 29:9467-9479(1990).
PubMed ID2248959

5AuthorsMcTigue M.A., Davies J.F. II, Kaufman B.T., Kraut J.
TitleCrystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin.
SourceBiochemistry 31:7264-7273(1992).
PubMed ID1510919

6AuthorsReyes V.M., Sawaya M.R., Brown K.A., Kraut J.
TitleIsomorphous crystal structures of Escherichia coli dihydrofolate reductase complexed with folate, 5-deazafolate, and 5,10-dideazatetrahydrofolate: mechanistic implications.
SourceBiochemistry 34:2710-2723(1995).
PubMed ID7873554

7AuthorsBolin J.T., Filman D.J., Matthews D.A., Hamlin R.C., Kraut J.
TitleDihydrofolate reductase. The stereochemistry of inhibitor selectivity.
SourceJ. Biol. Chem. 257:13650-13662(1982).
PubMed ID3880743



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