Dihydrofolate constitutive

C. Pharmacodynamics Folic acid is converted to tetrahydrofolate by the action of dihydrofolate reductase (Figure 33-2, reaction 3). One important set of reactions involving tetrahydrofolate and dihydrofolate constitutes the dTMP cycle (Figure 33-2, reaction 2), which supplies the dTMP required for DNA synthesis. Rapidly dividing cells, in which DNA must be rapidly synthesized, are highly sensitive to folic acid deficiency. For this reason, antifolate drugs are useful in the treatment of various infections and cancers. 

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

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