DHFR action

Mechanism of Action A folate antagonist that inhibits the enzyme dihydrofolate reductase (DHFR). Therapeutic Effect Disrupts purine, DNA, RNA, protein synthesis,... 

The action of trimethoprim (43) as an antibacterial depends on its inhibition of the bacterial enzyme dihydrofolate reductase (DHFR). The essential coenzyme tetrahydrofolate (47) operates in a cyclic process where the nucleotide thymidylate (48) is synthesized whilst... 

Folic acid is reduced within cells (principally the liver where it is stored) to tetrahydrofolate (THF also fhfolate) through the action of dihydrofolate reductase (DHFR), an NADPH-i equiring enzyme. 

Dietary folates must be chemically reduced to their tetrahy-dro forms, with four hydrogens on the pteridine ring, to be active. The enzyme responsible for this reduction is dihydrofolate reductase (DHFR), a key enzyme whose actions are inhibited by methotrexate and other antifolates. The result of this inhibition is depletion of intracellular pools of reduced folates (tetrahydrofolates) essential for thymidylate and purine synthesis. Lack of either thymidine or purines prevents synthesis of DNA. The DHFR-mediated effects of antifolate drugs on normal and probably also on cancerous cells may be neutralized by supplying reduced folates exogenously. The reduced folate used clinically for rescue is leucovorin (folinic acid), which bypasses the metabolic block induced by DHFR inhibitors. ... 

Using radioactive bicarbonate (l4C-NaHCC>3), we found it to be incorporated by infected red cells and free parasites into pyrimidines suggesting that P. lophurae synthesized cytosine, uracil and thymine de novo (Walsh and Sherman, 1968b). Further, evidence was found for the pyrimidine-pathway enzymes orotidine-5 -monophosphate pyropho-sphorylase (OMPDC also named orotidine-5 -decarboxylase) and thymi-dylate synthase (TS) in parasites but not in the red cells. The presence of TS made it possible for us to interpret the action of folic acid analogues in the same way as other microbes inhibition of DHFR would lead to a... 

Pemetrexed and its polyglutamates have a somewhat different spectrum of biochemical actions. Like methotrexate, it inhibits DHFR, but as a poly glutamate, even more potently inhibits glycinamide ribonucleotide formyltransferase (GART) and TS. Unlike methotrexate, it produces little change in the pool of reduced folates, indicating that the distal sites of inhibition (TS and GART) predominate. Its pattern of deoxynucleotide depletion also differs, with little effect on deoxyadenosine triphosphate (dATP), a profile more characteristic of primary TS inhibition. 

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