Regulation of ribonucleotide reductase

The regulation of ribonucleotide reductase is complex. The substrate-specificity and activity of the enzyme are controlled by two allosteric binding sites (a and b) in the R1 subunits. ATP and dATP increase or reduce the activity of the reductase by binding at site a. Other nucleotides interact with site b, and thereby alter the enzyme s specificity. 

Regulation of ribonucleotide reductase by both positive feedback from ATP and negative feedback by various 2 -deoxynucleoside triphosphates (eg, dATP) is tightly coupled to the need for DNA synthesis. 

FIGURE 22-42 Regulation of ribonucleotide reductase by deoxynu-deoside triphosphates. The overall activity of the enzyme is affected by binding at the primary regulatory site (left). The substrate specificity of the enzyme is affected by the nature of the effector molecule bound... 

The regulation of ribonucleotide reductase is complex, with many feedback reactions used to keep the supplies of deoxynu-cleotides in balance. For example, dGTP and dTTP are feedback inhibitors of their own formation. Each is also an activator of the synthesis of the complementary nucleotide (dCDP or dADP), while dATP is an inhibitor of the reductions to make dADP, dCDP, dGDP, and dUDP. These control functions keep the supply of deoxynu-cleotides in balance, so that a roughly equivalent amount of each remains available for DNA synthesis. 

Flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlates with down-regulation of ribonucleotide reductase M2 subunit. Clin. Cancer Res. 7 2527-36... 

The Synthesis of Deoxyribonucleotides Is Controlled by the Regulation of Ribonucleotide Reductase... 

Figure 25.16 Regulation of ribonucleotide reductase. (A) Each subunit in the R1 dimer contains two allosteric sites In addition to the active site. One site regulates ihe overall activity and the other site regulates substrate specificity,...

Regulation of ribonucleotide reductase is complex. The binding of dATP (deoxyadenosine triphosphate) to a regulatory site on the enzyme decreases catalytic activity. The binding of deoxyribonucleoside triphosphates to several other enzyme sites alters substrate specificity so that there are differential increases in the concentrations of each of the deoxyribonucleotides. This latter process balances the production of the 2 -deoxyribonucleotides required for cellular processes, especially that of DNA synthesis. 

See also Regulation of Ribonucleotide Reductase, Ribonucleotide Reductase and Deoxyribonucleotide Biosynthesis... 

Lack of ADA allows dATP to accumulate. High dATP levels inhibit production of the other dNTPs needed for DNA replication due to its effect on the regulation of ribonucleotide reductase. White blood cells, which must proliferate for an immune response to occur, and which have abundant salvage enzymes for making dATP, are most affected by lack of the enzyme. They are unable to proliferate, a necessary step for antibody production. 

See also Biosynthesis of Thymine Deoxyribonucleotides, Deoxyuridine Nucleotide Metabolism, Ribonucleotide Reductase and Deoxyribonucleotide Biosynthesis, Regulation of Ribonucleotide Reductase, Drug Design, Nucleotide Analogs in Medicine... 

Regulation of Ribonucleotide Reductase Activity (Figure 22.13, Table 22.2) Biosynthesis of Thymine Deoxyribonucleotides (Figure 22.17, Figure 22.18)... 

The regulation of ribonucleotide reductase is quite complex. The enzyme contains two allosteric sites, one controlling the activity of the enzyme and the other controlling the substrate specificity of the enzyme. ATP bound to the activity site activates the enzyme dATP bound to this site inhibits the enzyme. Substrate specificity is more complex. ATP bound to the substrate site activates the reduction of pyrimidines (CDP and UDP), to form dCDP and dUDP. The dUDP is not used for DNA synthesis rather, it is used to produce dTMP (see below). Once dTMP is produced, it is phosphorylated to dTTP, which then binds to the substrate site and induces the reduction of GDP. As dGTP accumulates, it replaces dTTP in the substrate site and allows ADP to be reduced to dADP. This leads to the accumulation of dATP, which will inhibit the overall activity of the enzyme. These allosteric changes are summarized in Table 41.3. 

The regulation of ribonucleotide reductase is quite complex. Assuming that an enzyme deficiency leads to highly elevated levels of dGTP, what effect would you predict on the reduction of ribonucleotides to deoxyribonucleotides under these conditions ... 

Some dairy propionibacteria also may find application in medicine, besides being a source of vitamin B12 for industry (see Section 7.2.1). P. shermanii is a useful model for studying die regulation of ribonucleotide reductase (RNR) activity, which has a direct role in die control of cell division. On the basis of RNR inhibitors tested in P. shermanii antitumor preparations were developed (Elford et al., 1979a, b). 

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