5,10-methylenetetrahydrofolate folate cycle

Methotrexate inhibits folate metabolism by preventing methylenetetrahydrofolate reductase from converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate thus inhibiting thymidylate synthase conversion of dUMP to dTMP. DNA replication is effectively decreased by the diminution of dTMP availability. As shown in Fig. 2, multiple enzymes mediate the folate cycle. Thus, genetic variation in these enzymes may... 

Continuing the folate cycle, THF reacts with serine to produce 5,10-methylenetetrahydrofolate, a reaction catalyzed by the vitamin B6-dependent enzyme serine/glycine hydrox-ymethyltransferase. 

H FIGURE 22-49 Thymidylate synthesis and folate metabolism as targets of chemotherapy, (a) During thymidylate synthesis, /V5,N10-methylenetetrahydrofolate is converted to 7,8-dihydrofolate the N5,N10-methylenetetrahydrofolate is regenerated in two steps (see Fig. 22-44). This cycle is a major target of several chemotherapeutic agents, (b) Fluorouracil and methotrexate are important chemotherapeutic agents. In cells, fluorouracil is converted to FdUMP, which... 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

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