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Function of Dihydrofolate Reductase

"Dihydrofolate reductase is a small enzyme that plays a supporting role, but an essential role, in the building of DNA and other processes. It manages the state of folate, a snaky organic molecule that shuttles carbon atoms to enzymes that need them in their reactions. Of particular importance, the enzyme thymidylate synthase uses these carbon atoms to build thymine bases, an essential component of DNA. After folate has released its carbon atoms, it has to be recycled. This is the job performed by dihydrofolate reductase." Molecule of the Month, 10/02, Goodsell, D.S.

Dihydrofolate reductase is an enzyme found in all organisms and catalyxes the NADPH-dependent redution of dihydrofolate to tertrahydrofolate by stereospecific hydride transfer from the NADPH cofactor to the C6 atom of the pterin ring.
The enzyme is instrumental in maintaing THF and THF derivitive levels within the cell.

THF and THF derivitive are essential for purine and thymidylate synthesis and consequently for cell growth and proliferation.
DHFR is the sole source of THF.

Because of this fact, DHFR can serve as an obstacle for rapidly proliferating cells--a.k.a cancer cells.

Interest in this enzyme originated from its role as a target in antibacterial, anticancer, and other clinically useful drugs.
DHFR is the target of the anticancer drug methotrexate (MTX), which is one of the most potent forms of chemotherapy used for the treatment of leukemias and lymphomas.

DHFR is also likely to be the target of MTX in the treatment of rheumatoid arthiritis.

Research of the enzyme has focused on investigating the linkage between protein dynamics and catalytic functions.

Techniques used to probe changes in protein dynamics in response to ligand bonding, conformation change, and mutagenesis include X-ray cystallography, NMR, and flouresence.

Figure 1 Dihydrofolate reductase catalyzed reaction. The (a) substrate 7,8-dihydrofolate (DHF), (b) cofactor NADPH, and (c) DHFR-catalyzed reactions are shown. In (c), only the pterin ring of the substrate/product and the nicotinamide ring of the cofactor are shown.

All inforamtion on the page comes from:

Schnell, J.R., Dyson J.H., and Wright, P.E. STRUCTURE, DYNAMICS, AND CATALYTIC FUNCTION OF DIHYDROFOLATEREDUCTASE (2004). Annual Review of Biophysics and Biomolecular Structure, 33:119-140.