Download DHFR catalyzes the transfer of a hydride from NADPH to

Dihydrofolate reductase, (DHFR)
Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to
tetrahydrofolic acid, using NADPH as electron donor, which can be converted to the kinds of
tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is
encoded by the DHFR gene. It is found in the q11→q22 region of chromosome 5.
Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding
diaminoheterocyclic molecules), but mammalian DHFRs are highly similar.[4] The plasmidencoded DHFR (R67 dihydrofolate reductase) shows a high level of resistance to the antibiotic
trimethoprim. It is a homotetramer with an unusual pore, which contains the active site, passing
through the middle of the molecule. Its structure is unrelated to that of chromosomal DHFRs.
A central eight-stranded beta-pleated sheet makes up the main feature of the polypeptide
backbone folding of DHFR. Seven of these strands are parallel and the eighth runs antiparallel.
Four alpha helices connect successive beta strands. Residues 9 – 24 are termed “Met20” or “loop
1” and, along with other loops, are part of the major subdomain that surround the active site.[8]
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 to be involved in the binding of substrate by
the enzyme.
Function
Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle
required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the
functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless
processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate
chromosomes
Mechanism
DHFR catalyzes the transfer of a hydride from NADPH to dihydrofolate with an accompanying
protonation to produce tetrahydrofolate. In the end, dihydrofolate is reduced to tetrahydrofolate
and NADPH is oxidized to NADP+. The high flexibility of Met20 and other loops near the
active site play a role in promoting the release of the product, tetrahydrofolate. In particular the
Met20 loop helps stabilize the nicotinamide ring of the NADPH to promote the transfer of the
hydride from NADPH to dihydrofolate.
Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to
therapeutic advantage.
DHFR can be targeted in the treatment of cancer. DHFR is responsible for the levels of
tetrahydrofolate in a cell, and the inhibition of DHFR can limit the growth and proliferation of
cells that are characteristic of cancer.
Methotrexate, a competitive inhibitor of DHFR, is one such anticancer drug that inhibits DHFR.
Other drugs include trimethoprim and pyrimethamine. These three are widely used as antitumor
and antimicrobial agents.