Dihydrofolate reductases (DHFRs) (EC 18.104.22.168)  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
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
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  to be involved in the binding of substrate by the enzyme.
We have also developed a profile, which covers the entire DHFR domain.
September 2007 / Text revised; profile added.
PROSITE methods (with tools and information) covered by this documentation:
Harpers' Review of Biochemistry, Lange, Los Altos (1985).
Knighton D.R., Kan C.-C., Howland E., Janson C.A., Hostomska Z., Welsh K.M., Matthews D.A.
Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase.
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