Folic acid metabolism and its disruption by pharmacologic agents

Folic acid metabolism in eukaryotic cells consists of a network of enzymatic reactions in which 1-carbon (C1) units at three different oxidation states are 1) interconverted while linked to the 5- and/or 10-positions of tetrahydrofolate, or 2) added to, or taken from, tetrahydrofolate. Particularly important in the latter category are reactions involving C1-tetrahydrofolate adducts in the synthesis of inosinate, thymidylate, serine, and methionine. Tetrahydrofolate, a central component of the network, can be generated from: 1) folate, via the NADPH-dependent dihydrofolate reductase; 2) 5-methyltetrahydrofolate via the methyl B12-dependent methionine synthetase; or 3) 5-formyltetrahydrofolate via a sequence of reactions beginning with the ATP-dependent isomerization to 5,10-methenyltetrahydrofolate or via transfer of the formyl group to glutamate. Because of the close relationship of folic acid metabolism to cell replication, folate-dependent enzymes provide excellent targets for cancer chemotherapy. This potential has not yet been realized, however, except for dihydrofolate reductase and thymidylate synthetase, which are strongly inhibited by the anti-cancer agents methotrexate (MTX) and FUra. The following enzymes are particularly attractive as targets for future exploitation in chemotherapy: 1) the two transformylases involved in purine nucleotide synthesis, 2) serine hydroxymethyltransferase, 3) methionine synthetase, and 4) methylenetetrahydrofolate dehydrogenase. Suggestions are also made for the development of new agents based upon a strategy of enzyme-targeted chemotherapy.