Ribonucleotide Reductase

The synthesis of new DNA within a cell requires the production of deoxynucleotides. The four required deoxynucleotides (adenosine, guanosine, cytidine, and thymidine) are all produced by reduction of the appropriate ribonucleotide substrate with ribonucleotide reductase, also referred to a nucleoside diphosphate reductase (NDPR) (Figure 3).13 The resulting oxidized form of NDPR can then be reduced back to NDPR by the action of glutaredoxin, which is in turn oxidized to thioredoxin.14

NDPR is a dimer, with each monomer made up of two subunits: a larger (M1) and a smaller (M2) subunit. The M1 subunit contains two allosteric sites involved in regulation of the overall activity of the enzyme and the enzyme's substrate specificity. The deoxynucleotide triphosphates bind to this allosteric site, and regulate their own synthesis. The M2 subunit is responsible for the key reduction reaction, carrying a tightly bound iron atom that stabilizes the tyrosyl free radical critical to reduction. Deoxynucleotide pools in proliferating cells are sufficient for only a few minutes of DNA synthesis without regeneration, thus making NDPR inhibition an attractive candidate for cancer chemotherapy.15

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