In search of dihydrofolate reductase

Dihydrofolate reductase is a fascinating enzyme.Nearly four decades after it was discovered in the late 1950s, the enzyme continues to command the attention of scientists in a variety of disciplines.Biochemists interested in protein structure and function appreciate the monomeric form and low molecular weight of dihydrofolate reductase (ca.20 kDa)-properties that make it an ideal subject for X-ray crystallography, NMR spectroscopy, kinetic measurements, and site-directed mutagenesis.Molecular biologists use the enzyme as a selectable genetic marker and as a model for gene amplification.Oncologists take advantage of the identification of dihydrofolate reductase as the target for Methotrexate to design optimal regimens for use of the drug in cancer chemotherapy.Information about structural features of the enzyme that account for the tight binding of Methotrexate and alterations in structure or amount of the enzyme that are responsible for drug resistance provides guidance to pharmacologists, as Hitchings (1989) pointed out in his Nobel Lecture, for the design of anti-folates directed against tumors,