Nucleoside kinases

Showdomycin. Showdomycin (2-p-D-ribofuranosyhnaleimide) (7) is a maleimide C-nucleoside antibiotic synthesi2ed by S. showdoensis-, isoshowdomycin (8) and maleimycin (9) have also been isolated (1—6). Showdomycin is not phosphorylated by nucleoside kinase and is not a substrate for nucleoside phosphorylase. Once (7) enters the cell, it blocks the uptake of glucose and other nutrients. 

Entecavir, telbivudine, clevudine, and the other nucleoside analogues (Fig. 4aa) need to be phosphorylated to their 5 -triphosphate form to be antivirally active (Fig. 8). This again implies three phosphorylation steps based successively on a nucleoside kinase, nucleoside 5 -monophosphate kinase, and nucleoside 5 -diphosphate kinase. These reactions have been characterized only in a few cases, that is, thymidylate kinase in the metabolism of clevudine (Hu et al. 2005). 

Dideoxyuridine (ddU) is an antiviral agent that proved ineffective at controlling human immunodeficiency virus type 1 (HIV-1) infection in human T-cells. This ineffectiveness was ascribed to a lack of substrate affinity of ddU for cellular nucleoside kinases, which prevent it from being metabolized to the active 5 -triphosphate. To overcome this problem, bis[(pivaloyloxy)methyl] 2, 3 -dideoxyuridine 5 -monophosphate (9.41) was prepared and shown to be a membrane-permeable prodrug of 2, 3 -di-deoxyuridine 5 -monophosphate (ddUMP, 9.42) [93]. Indeed, human T-cell lines exposed to 9.41 rapidly formed the mono-, di-, and triphosphate of ddU, and antiviral activity was observed. This example again documents... 

The phosphoribosyltiansferases The nucleoside kinases Nucleoside phosphokinases Nucleotide reductases Methylases and demethylases Other anabolic enzymes Catabolism... 

Tin- BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES The nucleoside kinases... 

Gemcitabine is intracellularly activated by nucleoside kinases to diphosphate and triphosphate nucleosides. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase while gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine is used for the treatment of non-small cell lung carcinoma and of adenocarcinoma of the pancreas. It has to be administred intravenously and is eliminated by metabolism with an elimination half-life of approximately 50 minutes. Its spectrum of adverse effects is comparable to that of 5-FU. 

Enzymes found in both parasites and humans, but essential to parasite life while being nonessential or less essential to human life (e.g., purine nucleoside kinase, ornithine decarboxylase)... 

Tyron, V.V. Pollack, D. Purine metabolism in Acholeplasma laidlawii B novel PPi-dependent nucleoside kinase activity, J, BacterioL, 159, 265-270 (1984)... 

Tyron, V.V. Pollack, J.D. Distinction in mollicutes purine metabolism pyrophosphate-dependent nucleoside kinase and dependence on guanylate salvage. Int. J. Syst. BacterioL, 35, 497-501 (1985)... 

Nucleophilic alkylation, C=0, C=N, and enones, 9, 192 Nucleophilic substitutions Sn2 processes, 9, 520, 9, 5249, 548-549 SnI processes, 10, 684 Sn2 processes, 10, 684 with titanium alkoxide complexes, 4, 273 Nucleoside dimers, via cross metathesis, 11, 194 Nucleoside kinases, in medicinal chemistry, 12, 458 Nucleosides, iodinated, into zinc reagents, 9, 82-83... 

Purine nucleoside kinase Trichomonas vaginalis and Entamoeba histolytica None... 

Gemcitabine is phosphorylated initially by the enzyme deoxycytidine kinase and then by other nucleoside kinases to the di- and triphosphate nucleotide forms, which then inhibit DNA synthesis. Inhibition is considered to result from two actions inhibition of ribonucleotide reductase by gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA and incorporation of gemcitabine triphosphate into DNA. Following incorporation of gemcitabine nucleotide, only one additional nucleotide can be added to the growing DNA strand, resulting in chain termination. 

The compound 5-fluorouridine targets thymidylate synthase. After a nucleoside kinase phosphorylates it, resembles the natural substrate for the enzyme, except that it contains a fluorine where dUMP has a hydrogen. The fluorine isn t removed from the ring by thymidylate synthase, and this causes the ring to remain covalently bound to the enzyme, which means that the enzyme is irreversibly inactivated. The 5-fluorouridine monophosphate is an example of a suicide substrate —a compound whose reaction with an enzyme causes the enzyme to no longer function. 

PolyP3 was found to be a phosphodonor for the phosphorylation of some proteins in rat liver microsomes (Tsutsui, 1986) and for nucleoside kinases, in particular human deoxyri-bonucleoside kinases (Krawiec et al, 2003). This gives an additional possibility for the involvement of PolyPs in the regulatory processes in animal cells. 

NRTIs are phosphorylated and converted into diphosphate forms by nucleoside kinases. These acdvated forms have high levels of afdnity for HTV-1 reverse d anscriptase and compete with the natural deoxynucleoside diphosphates. Once incorporated into the growing chain of DNA, lack of a 3 -hydroxyl group that can form a phosphodiester bond with the incoming nucleoside causes chain terminadon. Tenofovir is an exception in this group as it is a nucleotide analogue rather than nucleoside and, as such, requires only tw o phosphorylation steps instead of three to become the active form. Pharmacological characteristics of FDA approved NRTIs are presented in Table 41.3. 

A quantitatively less significant salvage pathway uses purine nucleoside phosphorylase and nucleoside kinase ... 

Nucleoside kinases specific for inosine or guanosine have been described. Adenosine kinase is widely distributed in mammalian tissues. 

Purine and Pyrimidine Analogues - The following comments will center upon work published in 1966 Heidelberger has included earlier work in this area in his recent review. Modifications of 6-mercaptopurine (I) are of continuing interest because of mereaptopurine s activity in human leukemia, and the ultimate development of resistance by the leukemic cells to this drug. 6-methylmercaptopurine riboside (II) is converted to 6-methyImercaptopurine ribonucleotide (III) by a nucleoside kinase. Cells... 

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