Deoxythymidine monophosphate biosynthesis

Folic acid serves as a carrier of one-carbon groups in many metabolic reactions. It is required for the biosynthesis of compounds such as choline, serine, glycine, purines, and deoxythymidine monophosphate (dTMP). 

The best-known example of this type of inhibition is 5 -fluorouracil, a rather old cytostatic agent. Fluorouracil is first converted metabolically into the corresponding phosphodeoxyriboside. This, in turn, blocks DNA biosynthesis by inhibiting thy-midylate synthase, an enzyme which methylates deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), one of the four building blocks of DNA [77]. 

Folate (foUc acid) is an essential vitamin which, in its active form of tetrahydrofolate (THF, Figure 4-1), transfers 1-carbon groups to intermediates in metaboUsm. Folate plays an important role in DNA synthesis. It is required for the de novo synthesis of purines and for the conversion of deoxyuridine 5-monophosphate (dUMP) to deoxythymidine 5 -monophosphate (dTMP). Additionally, folate derivatives participate in the biosynthesis of choline, serine, glycine, and methionine. However, in situations of folate deficiency, symptoms are not observed from the lack of these products as adequate levels of chohne and amino acids are obtained from the diet. (See also Case 3.)... 

Thymidylate synthase (TS) is a highly conserved, 70 IcDa dimeric protein that catalyzes the reductive methylation of 2 -deoxyuridine 5 -monophosphate (dUMP) by 5,10-methylene-5,6,7,8-tetrahydrofolate to give 2 -deoxythymidine 5 -monophosphate (dTMP) and 7,8-dihydrofolate. Because TS plays a crucial role in DNA biosynthesis, it has been the focus of intense chemical, biological, and clinical research aimed at generating novel antitumor drugs with properties different from those of other antifolates such as methotrexate, which acts by inhibiting dihydrofolate reductase. 

Biosynthesis of thymine nucleotides. This is shown in Fig. 2. Since thymine is a constituent of DNA, the corresponding nucleotides contain 2-deoxyribose. Thymidylic acid (TMP) is therefore more correctly dTMP (deoxythymidine 5 -monophosphate). The reaction sequence is CMP - CDP - dCDP -v dCMP ->dUMP- TMP (dTMP)- TDP (dTDP)- TTP (dITP). Methylation of dUMP to TMP is catalysed by th idylate synthase (EC 2.1.1.45). The cofiictor, AP,A/ -methylenetetrahydrofolic acid, transfers the active Cl unit to C5 of dUMP, and it also functions as a reducing agent in the formation of the methyl group from the active Cl unit. 

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