The Design and Optimization
of Novel Human Dihydrofolate Reductase Inhibitors for the Management of Proliferative Disease
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Tetrahydrofolate, a derivative of Vitamin B9, acts a one-carbon donor during reactions necessary for the synthesis of essential nucleotide precursors. One of the enzymes which makes use of such metabolites, is Thymidylate synthesase, which is the only enzyme utilising one-carbon-transfers that in the end fails to produce tetrahydrofolate. It instead produces Dihydrofolate the reduced and insufficient form of folate. The Dihydrofolate reductase enzyme (DHFR) is the enzyme that recycles the dihydrofolate to tetrahydrofolate via a redox reaction. DHFR has a crucial role in cellular proliferation,...
Tetrahydrofolate, a derivative of Vitamin B9, acts a one-carbon donor during reactions necessary for the synthesis of essential nucleotide precursors. One of the enzymes which makes use of such metabolites, is Thymidylate synthesase, which is the only enzyme utilising one-carbon-transfers that in the end fails to produce tetrahydrofolate. It instead produces Dihydrofolate the reduced and insufficient form of folate. The Dihydrofolate reductase enzyme (DHFR) is the enzyme that recycles the dihydrofolate to tetrahydrofolate via a redox reaction. DHFR has a crucial role in cellular proliferation, as inhibition of this ubiquitous enzyme leads to cessation of cellular growth. This makes the DHFR enzyme an ideal target in humans for inhibiting proliferation in rapidly dividing cells, with clinical sequelae in conditions such as rheumatic disease, Crohn's disease, and malignant disease.
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