Ribonucleotide, biosynthesis structures

Hydroxyurea interferes with the synthesis of both pyrimidine and purine nucleotides (see table 23.3). It interferes with the synthesis of deoxyribonucleotides by inhibiting ribonucleotide reductase of mammalian cells, an enzyme that is crucial and probably rate-limiting in the biosynthesis of DNA. It probably acts by disrupting the iron-tyrosyl radical structure at the active site of the reductase. Hydroxyurea is in clinical use as an anticancer agent. 

Ribonucleotide reductases (RNR) constitute a large group of essential enzymes with a diverse array of primary as well as quaternary structures. Common for the enzymes is that they catalyze the rate-determining step in DNA biosynthesis, the reduction of ribonucleotides into deoxy-ribonucleotides (Figure 19) [44,45]. 

Ribonucleotide Reductase. The ribonucleotide reductases catalyze the reduction of ribonucleoside-diphosphates (or triphosphates) to the corresponding 2 -deoxyribonucleoside-diphosphates (or triphosphates), processes of preeminent importance for the biosynthesis of DNA (see Table 2, entry 4) (65,86). A variety of metal-containing cofactors have been discovered in the ribonucleotide reductases investigated to date (eg, a binuclear iron center in the mammalian and in the E. coli ribonucleoside diphosphate reductase) and the oxidation of two protein thiols to a disulfide unit is indicated as the direct source of the two reduction equivalents. The reductase from Lactobacillus leichmanii employs coenzyme B12 as cofactor in its (normal) base-on form and acts on purine- or pyrimidine-based ribonucleoside-triphosphates. Its crystal structure reveals not only the arrangement of the bound corrinoid cofactor, but also how the enzyme is... 

The thiosemicarbazones (Structure 62, Figure 6.2) have antitumour activity in their own right [62]. Early mechanistic studies led to the postulate that the mode of action is by inhibition of ribonucleotide reductase [63, 64]. This metal-dependent enzyme is a key intermediate in DNA biosynthesis because it converts ribonucleotides to deoxyribo-nucleotides [65,66]. 

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