Ribonucleoside Diphosphate Reductases

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... 

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. 

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). 

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. ... 

Durham, L. J., Larsson, A., and Reichard, P., 1967, Enzymatic synthesis of deoxyribonu-cleotides II. The mechanism of hydrogen transfer of the ribonucleoside diphosphate reductase system from Escherichia coli studied with nuclear magnetic resonance. European J. Biochem. I 92n95. 

Eriksson, S., Sj berg, B.-M., and Hahne, S., 1977, Ribonucleoside diphosphate reductase from Escherichia coli. An immunological assay and a novel purification from an overproducing strain lysogenic for phage Xdnrd. J. Biol. Chem. 252 613296138. 

Stubbe, J., and Ackles, D., 1980, On the mechanism of ribonucleoside diphosphate reductase from Escherichia coli. Evidence for 3i-C-H bond cleavage. J. Biol. Chem. 255 8027n8030. 

B. Ribonucleoside Diphosphate Reductase Induced in E. coli by Infection with Bacteriophage T4... 

C. Ribonucleoside Diphosphate Reductase from Mammalian Sources... 

Deoxy-2 -fluoromethylene nucleosides are potential inhibitors of ribonucleoside diphosphate reductase (RDPR), which catalyzes the essential biosynthesis path of deoxyri-bonucleoside in the DNA synthesis system. Initial hydrogen abstraction at the C-3 position by tyrosyl radical has been proposed for the RDPR catalysis system (see from 71 to 73 in... 

In this case, the biological target was ribonucleoside diphosphate reductase and it was proposed on the basis of this result that before the compound interacts with the enzyme, it should form a complex with the Fe(II) ion. 

Fig. 56. Mechanism proposed for inactivation of ribonucleoside-diphosphate reductase by 2 -azido-2 -deoxyuridine 5 -diphosphate (26).

As seen in Figure 22.12, rNDPs ("D" here refers to di-) are all converted to dNDPs by the enzyme ribonucleoside diphosphate reductase (also called ribonucleotide reductase, rNDP reductase, or RNR). The relatively simple routes giving rise to dATP, dGTP, and dCTP, are in contrast to the involved mechanism for dTTP. Note that dUDP is a precursor of dTTP. 

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