Deoxyuridylic acid

Thymine is found only in DNA but not in RNA. Deoxythymidylic acid is formed by methylation of deoxyuridylic acid this may be an indication that ribonucleosides were present on the young Earth before the deoxynucleosides. 

Several possible mechanisms of resistance to 5-fluo-rouracU have been identified, including increased synthesis of the target enzyme, altered affinity of thymidy-late synthetase for FdUMP, depletion of enzymes (especially uridine kinase) that activate 5-fluorouracil to nucleotides, an increase in the pool of the normal metabolite deoxyuridylic acid (dUMP), and an increase in the rate of catabolism of 5-fluorouracil. 

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

U UDP UDPGA dUMP UdRP Uracil Uridine diphosphate Uridine diphosphate glucuronic acid Deoxyuridylate-5 -monophosphate Deoxyuridylic acid... 

Deoxyribose Deoxyuridine Deoxyuridylic acid deoxyuridine monophosphate (dUMP) Deoxyuridine diphosphate (dUDP) Deoxyuridine triphosphate (dUTP)... 

Figure 10.11 Biosynthesis of thymidylic acid from deoxyuridylic acid.

Fluorouracil [flure oh YOOR a sil] (5-FU), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of one of the essential precursors for DNA synthesis. 

Uracil, U Uridylic acid, UMP Deoxyuridylic acid, dUMP... 

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),... 

Fig. 4.21)—used to treat breast cancer and skin cancer. The target enzyme is thymidylate synthetase which catalyses the conversion of 2 -deoxyuridylic acid to dTMP (Figs 4.21 and 4.22). 

Thymidylate synthetase is an important enzyme, which is responsible for the reductive methylation of deoxyuridylic acid (dUMP, 7) to deoxythymidylic acid (dTMP, 8). The methylation of the uracil moiety (present in RNA) to 5-methyl uracil (thymine, present in DNA) requires participation of a folic acid coenzyme, N, methylenetetrahydrofolate as a methyl donor. The functioning of thymidylate synthetase is coupled with the activity of DHF reductase. That is why this biochemical target is usually referred to as thymidylate synthetase/ DHF reductase. 

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). 

Fluorouracil (5-FU) interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid to thymidylic acid. Topical formulations (carac, efudex, fluoroplex) are used in multiple actinic keratoses, actinic cheilitis, Bowen s disease, and superficial basal cell carcinomas not amenable to other treatments. 

Ludwig P S, Schwendener R A, Schott H (2005). Synthesis and anticancer activities of amphiphilic 5-fluoro-2 -deoxyuridylic acid prodrugs. Euro. J. Med. Chem. 40 494-504. 

Uracil U Uridylic acid UMP Deoxyuridylic acid dUMP... 

Polymers 4a and 4b are the analogues to the poly(deoxyuridylic acid) and poly(thymidylic acid), respectively, in which methylene diphosphate groups are substituted by 1,2-dicarboxyethylene groups. Polymer 6 is also an analogue to poly(thymidylic acid) whose methylene diphosphate groups are substituted by 1,2-dihydroxyethylene groups. 

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. 

Thymine and thymidine are needed to replace folic acid for Streptococcus faecalis, and cells grown on thymine had no detectable folic acid activity for Lactobacillus casei (Stokes, 1944a,b). The inference was that FA was necessary for the s5mthesis of thymine (or thymidine). The site of the folic reaction was soon recognized to be the 5-methyl carbon. Friedkin and Korn-berg (1957) found that P -labeled deoxyuridylic acid was converted to labeled thymidylic acid by extracts of Escherichia coli. As repeatedly the case in many folic-catalyzed cell-free systems, treatment with Dowex-1 stopped the reaction. It was restored by a boiled extract of E. coli, in turn replaceable by FH4. A preliminary note confirms these results (Greenberg and Humphreys, 1958). 

Modifications before the base symbol concern the base, those after the base symbol concern the sugar. Therefore d(fl U) is d(fl U) or poly-5-fluoro-deoxyuridylic acid, but d(Ufl) is d(Ufl) or poly-2 deoxy-2 -fluoro-uridylic acid r(e U) is r(e U) or poly-5-ethyl-uridylic acid, but r(U e) is r(U e) or poly-2 -0-ethyl-ribo-uridylic acid etc. etc. 

Friedkin, M. (1957) Enzymatic conversion of deoxyuridylic acid to thymidylic acid and the participation of tetrahydrofolic acid, Fed. Proc., 16 183. 

Heat transition from the double helix to separate strands is accompanied by an increase of UV absorption. The melting profiles of the complexes, shown in Fig. 9, are quite similar to those of the relevant natural complexes. The melting temperature of 21U-poly(dA) was found to be 62 °C, a little lower than that (65 °C) of the natural polymer complex, poly(dA)-poly(deoxyuridylic acid) [poly(dU)] [41]. 

Deoxyuridylic acid -f-6,10< Bb—FH. Thymidylic acid - -FH, Thymidylate synthetase ( d)... 

Fluorine has the closest atomic dimensions to the hydrogen atom, and pyrimidine analogues where hydrogen is substituted by fluorine are powerful antimetabolites. 5-fluoro-orotic acid (Fig. 12), for instance, prevents the conversion of orotic acid to orotidylic acid (Fig. 2) and the methylation of deoxyuridylic acid to form thymi-dylic acid (Fig. 9). 

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