Ribonucleoside reductase

Hydroxycarbamide (hydroxyurea) is an inhibitor of the enzyme ribonucleoside reductase which catalyzes the conversion of ribonucleotides to deoxyri-bonucleotides, a crucial step in the biosynthesis of DNA. The drug is S-phase specihc. Resistance can occur by an increase of ribonucleohde reductase. 

Hydroxyurea. It is believed that hydroxyurea (Hydrea) impairs DNA synthesis by inhibiting a specific enzyme (ribonucleoside reductase) involved in synthesizing nucleic acid precursors.11 The uses of hydroxyurea are listed in Table 36-7. 

This reaction is accomplished by several types of iron ribonucleoside reductase (RNR) [1,5,7,13,118], One of the best-characterized RNRs (from E. coli) contains two homodimeric protein components, R1 and R2. The R2 protein comprises an oxygen bridged dinuclear Fe(III) in its oxidized form [119], All RNRs promote the formation of a stable organic radical, which, eventually, leads to the abstraction of a hydrogen atom from the ribose. In the case of E. coli RNR, the latter is accomplished by the R1 protein, specifically by a cysteinyl residue a redox active cystine, also part of Rl, provides the required reducing equivalents (Figure 25). 

Inactivates ribonucleoside reductase and blocks the synthesis of deoxynucleotides, thus inhibiting DNA synthesis and inducing cell death. 

Vidarabine is an inhibitor of viral DNA synthesis. Cellular enzymes phosphorylate vidarabine to the triphosphate, which inhibits viral DNA polymerase activity in a manner that is competitive with deoxyadenosine triphosphate. Vidarabine triphosphate is incorporated into both cellular and viral DNA, where it may act as a chain terminator. Vidarabine triphosphate also inhibits ribonucleoside reductase, RNA polyadenylation, and 5 -adenosylhomocysteine hydrolase, an enzyme involved in transmethylation reactions. Resistant variants due to mutations in viral DNA polymerase can be selected in vitro. 

Brunella, A., Abrantes, M., and Ghisalba, O. (2000) Preparative 2 -reduction of ATP catalyzed by ribonucleoside reductase purified by liquid-liquid extraction. 

Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. Cancer Res 1968 28 1559-1565. 

The deoxyribonucleotides, except for deoxythymidine nucleotide, are formed from the ribonucleotides by the action of an enzyme complex, which comprises two enzymes, ribonucleoside diphosphate reductase and thioredoxin reductase (Figure 20.11). The removal of a hydroxyl group in the ribose part of the molecule is a reduction reaction, which requires NADPH. This is generated in the pentose phosphate pathway. (Note, this pathway is important in proliferating cells not only for generation... 

Ribonucleotide reductase (diphosphate) [EC 1.17.4.1], also known as ribonucleoside-diphosphate reductase, catalyzes the reaction of a 2 -deoxyribonucleoside diphosphate with oxidized thioredoxin and water to produce a ribonucleoside diphosphate and reduced thioredoxin. This system requires the presence of iron ions and ATP. Ribonucleotide reductase (triphosphate) [EC... 

C. Formation of deoxyribonudeotides by reduction of the 2 -hydroxyl group of the ribose sugars on the ribonucleoside diphosphates ADP and GDP is catalyzed by ribonucleotide reductase (Figure 10-3). 

The primary action is inhibition of enzyme ribonucleoside diphosphate reductase. The drug is specific for S phase of the cell cycle and causes cell to arrest at the Gj-S interface. 

Cory, J. G. (1989). Role of ribonucleotide reductase in cell division. In Inhibitors of Ribonucleoside Diphosphate Reductase Activity (J. G. Cory and A. H. Cory, eds.), pp. 1-16. Pergamon, New York. 

The nucleotides described thus far in this chapter all contain ribose (ribonucleotides). The nucleotides required for DNA synthesis, however, are 2 -deoxyribonucleotides, which are produced from ribonucleoside diphosphates by the enzyme ribonucleotide reductase. 

Ribonucleotide reductase ribonucleoside diphosphate reductase) is a multisubunit enzyme (two identical B1 subunits and two identical B2 subunits) that is specific for the reduction of nucleoside diphosphates (ADP, GDP, CDP, and UDP) to their deoxy-forms (dADP, dGDP, dCDP, and dUDP). The immediate donors of the hydrogen atoms needed for the reduction of the 2-hydroxyl group are two sulfhydryl groups on the enzyme itself, which, during the reaction, form a disulfide bond (Figure 22.12). 

Deoxyribonucleotides. A chain involving NADPH, a flavoprotein, thioredoxin, and ribonucleotide reductase converts either the ribonucleoside diphosphates or triphosphates to the corresponding 2-deoxy forms (step j, Fig. 25-14) as indicated in Eq. 25-16. 

Formylpurine thiosemicarbazone is a potent inhibitor of ribonucleoside diphosphate reductase and is active against herpes simplex and cytomegalovirus132), but is nephrotoxic. Attempts, so far unsuccessful, have been made to prepare derivatives which possess an antitumour effect but are less toxic133). 

Hydroxyurea suppresses DNA synthesis by inhibiting ribonucleoside diphosphate reductase, which catalyzes the reduction of ribonucleotides to deoxyribonucleotides. Hydroxyurea is used in chronic cases of granulocytic leukemia that are unresponsive to busulfan. In addition, it is used for acute lymphoblastic leukemia. Hydroxyurea may cause bone marrow depression. 

The other thiosemicarbazones are less well studied and as yet the link between antiviral action and chelation is not fully established. It has been proposed that the chelation of iron(II), a cofactor of ribonucleoside diphosphate reductase, could be the principal mode of action of the thiosemicarbazones300. However, other mechanisms are possible. Investigations of the ESR spectra of copper(II) complexes of thiosemicarbazones has been used to follow the intracellular reactions of the complexes - see Antholine et al.301 for a review. In Ehrlich cells the chelate becomes localized in the cell membrane302. This spectroscopic technique could also be used to monitor the antimala-rial action of 2-acetylpyridine thiosemicarbazones303. ... 

Ribonucleotide reductase uses ribonucleoside diphosphates (ADP, GDP, CDP, and UDP) as substrates and reduces the 2 position of ribose. 

Inhibition of DNA synthesis is brought about by the action of dTTP as an allosteric inhibitor of ribonucleotide reductase (Reichard et al., 1961 Moore and Hurlbert, 1966 Brown and Reichard, 1969 Rummer et al., 1978). This enzyme is responsible for reducing all four ribonucleoside diphosphates (NDP) to the corresponding de-oxyribonucleoside diphosphates (dNDP). It is subject to a complex allosteric control which has been most studied with the bacterial enzyme. Most studies with the mammalian enzyme show it to be similar to the bacterial enzyme (Fig.11.7). 

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