Deoxyuridylate metabolism

Fluorodl is metabolized by the same route to 5-fluoro- — 2-deoxyuridylic acid (FUdRP)... 

A more complete and refined diagram of 1-carbon metabolism is given by Figure 9,6, The cycle of reactions that regenerate methionine is shown at the center, as in the previous diagrams, Thymidylate synthase (TS), at the left, catalyzes the conversion of deoxyuridylic acid (dUMF) to thymidylic acid (dTMP),... 

Fluorouracil is a pyrimidine antimetabolite. The metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to chymidylic acid. In this manner, fluorouracil interferes with the synthesis of DNA and to a lesser extent inhibits the formation of RNA. It is indicated in colon, rectum, breast, gastric, and pancreatic carcinoma (injection) multiple actinic or solar keratoses, and superficial basal-cell carcinoma (topical). 

One of the most well-known examples of effective replacement of hydrogen with fluorine is observed in the antineoplastic drug 5-fluorouracil (Figure 2.1). This compound is metabolized in vivo to 5-fluoro-2 -deoxyuridylic acid (5-fluoro-dUMP), which is the active drug that covalently binds to thymidylate synthase, the enzyme responsible for the essential conversion in DNA synthesis of uridylic acid to thymidylic acid. 

Metabolism of the pyrimidine deoxyribonucleotides is more complex because, in addition to transfer of phosphoryl groups, deamination and methylation reactions occur at this level. Specifically, the thymidine phosphates are derived by methylation of deoxyuridylate, and the latter may be derived from the deoxycytidine phosphates by way of deoxycytidylate deaminase. The deoxycytidine phosphates are not formed by amination of deoxyuridine phosphates, but are derived entirely from the cytidine phosphates by enzymatic reduction (Chapter 16). 

Both the pyrimidines and the purines are built up from small precursor molecules which are readily available in the metabolic pool (page 185). The free bases are not synthesized as such but, while being assembled, the partially constructed ring structure reacts with a special phosphorylated pentose known as PRPP (5-phosphoribosyl-l-pyrophosphate) and forms a ribonucleotide. The deoxyribonucleotides, with the exception of TMP which is formed by methylation of deoxyuridylate, are formed by reduction of the corresponding ribonucleoside diphosphate. The conversion is precisely controlled by allosteric effects which ensure that all four deoxyribonucleotides are available in amounts appropriate for nucleic acid synthesis. 

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