Uridine kinase

The purine and pyrimidine bases can be converted to then-respective nncleotides by reaction with 5-phosphoribosyl 1-pyrophosphate. Since these bases are not very soluble, they are not transported in the blood, so that the reactions are only of qnantitative significance in the intestine, where the bases are produced by degradation of nucleotides. In contrast, in some cells, nucleosides are converted back to nucleotides by the activity of kinase enzymes. In particular, adenosine is converted to AMP, by the action of adenosine kinase, and uridine is converted to UMP by a uridine kinase... 

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. 

Fig. lA. Anabolic and catabolic pathways of 5-FU. DPD dihydropyrimidine dehydrogenase, DP di-hydropyrimidinase, pUP beta-ureidopropionase, UP uridine phosphorylase, OPRT orotate phospho-ribosyl transferase, UK uridine kinase, TP thymidine phosphorylase, TK thymidine kinase, RNR ribonucleotide reductase. The three active metabolites (shown in rectangles) are FdUMP (5-fluoro-2 -deoxyuridine 5 -monophosphate) inhibiting TS (thymidylate synthase), and FUTP (5-fluorouridine 5 -triphosphate) and FdUTP (5-fluoro 2 -deoxyuridine 5 -triphosphate) interfering with RNA and DNA, respectively. 

Ellipticine inhibits DNA, RNA and protein synthesis. The inhibition is not reversible by removal of the alkaloid. It has no appreciable effects on thymidine and uridine kinases or on RNA polymerase, but it markedly inhibits DNA polymerase activity [240, 241]. The actual mechanism of action of ellipticine and related compounds has not yet been elucidated. Ellipticine and derivatives have been found to interact with bacterial membranes [242]. Many investigators have categorized these compounds as DNA-interacting or intercalating agents [230, 235, 237,243-246]. It has recently been postulated that mammalian DNA topoisomerase II may be a common target of these antitumour compounds [247],... 

The concept that oestrogens stimulate cell proliferation directly arises mainly from the observation that physiological concentrations of oestrogens stimulate both the de novo and salvage pathways of DNA synthesis as well as inducing a number of enzymes intimately involved in DNA synthesis and including DNA polymerase, thymidine and uridine kinases, thymidilate synthetase and dihydrofolate reductase. There is evidence that some of these enzymes may be regulated at the transcrip-... 

Once inside the cell, the nucleoside is converted to the corresponding NMP, adenosine by adenosine kinase and uridine by uridine kinase ... 

Greenberg, N., Schumm, D.E., and Wehh, T.E. (1977) Uridine kinase activities and pyrimidine nucleoside phosphorylation in fluoropyrimidine-sensitive and -resistant cell lines of the Novikoff hepatoma. The Biochemical Journal, 164 (2), 379-387. 

The action of vinblastine and vincristine on enzyme systems has been studied. Both alkaloids strongly inactivate pH-5-enzymes and DNA-dependent RNA polymerase. In contrast, DNA polymerase and uridine kinase are hardly influenced. Despite successful studies on phenomena of Vinca alkaloid... 

Fluorouracil (5-FU) requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity. Several routes are available for the formation of floxuridine monophosphate (FUMP). 5-FU may be converted to fluorouridine by uridine phos-phorylase and then to FUMP by uridine kinase, or it may react directly with 5-phosphoribosyl-l-pyrophosphate (PRPP), in a reaction catalyzed by orotate phosphoribosyl transferase, to form FUMP. Many metabolic pathways are available to FUMP. As the triphosphate FUTP, it may be incorporated into RNA. An alternative reaction sequence... 

Deletion of uridine kinase Deletion of nucleoside phosphorylase Deletion of orotic acid phosphoribosyltransferase Increased thymidylate kinase... 

Trypanosoma brucei complex. African trypanosomes of the Trypanosoma brucei complex metabolize pyrimidines in a manner similar to that of Leishmania and T. cruzi (Fig. 6.17). All six enzyme activities for the synthesis of UMP were detected in homogenates of blood trypomastigotes of T.b. brucei (87). In addition, uracil PRTase, cytidine deaminase, and pyrimidine cleavage activities have been detected in cell-free homogenates no uridine kinase activity was detected (94). 

Evidence for pyrimidine de novo biosynthesis has also been found in other trematodes. Its enzymes are present in Fasciola gigantica (81), Paragonimus ohirai (112) and Clonorchis sinensis (112). De novo biosynthesis was verified by demonstrating the incorporation of [ C]bicarbonate into the C-2 position of uracil in P. ohirai (112). The pyrimidine salvage enzymes, uridine kinase and thymidine kinase, are found in P. ohirai and C. sinensis extracts (112). Aspartate transcarbamoylase is found in Fasciola hepatica and Paramphistomum cervi extracts (113). 

Treatment of bromomethyl acetate with the sodium salt of a dialkyl phosphite, followed by deacetylation with methoxide affords the corresponding dialkyl hydroxymethanephosphonate. If this is tosylated with tosyl chloride, and the product treated with nucleosides [protected at the 3 -(and 2 -, if present) hydroxy groups] and sodium hydride in DMF, the monoalkyl ester of a 5 -0-phosphonyl-methyl nucleoside (60) is obtained after deblocking the sugar, and subsequent dealkylation with TMS-iodide affords (61). Like alkyl esters of 5 -mononucleotides, (60) is resistant to acid and alkaline hydrolysis, while (61) is stable in acidic and alkaline media, and is also resistant to hydrolysis by alkaline phosphomono-esterase and snake venom 5 -nucleotidase. Treatment of (61) with DCC and morpholine, and subsequently with orthophosphate or pyrophosphate, affords (62) and (63), respectively. Alkaline phosphomonoesterase from E. co/i hydrolyses the pyrophosphate links in (62) and (63) to give (61) and orthophosphate. The UTP and CTP analogues (63 B = U or C) are inhibitors of uridine kinase from... 

---