Selective inhibition of non-haem-containing enzymes

Ribonucleotide reductase catalyses the reduction of the four common ribonucleotides to their corresponding deoxyribonucleotides, an essential step in DNA synthesis. All four ribonucleotides are reduced by the same enzyme [77], The enzyme (250 000 mol. wt.) is a complex of two proteins Mi which contains substrate and redox-active sulphydryl groups and M2 which contains both a (x-oxo-bridged binuclear iron centre (Fig. 5) [77] and a tyrosine moiety sidechain which exists as a free radical stabilised by the iron centre [78], This radical, which is only 5.3 A away from iron centre 1, has access to the substrate-binding pocket and is essential for enzyme activity. Electrons for the reduction reaction are supplied from NADPH via thioredoxin, a small redox-active protein. 

A wide range of iron chelators have been shown to inhibit ribonucleotide reductase [79,80] and this is undoubtedly the reason for cytotoxic properties of many such molecules. Some iron chelators may also function as free radical scavengers, for instance, hydroxyurea which inhibits the enzyme by the latter mode of action. Such agents hold the cell cycle in the S-stage because the synthesis of DNA is inhibited. The ability of iron chelators to inhibit ribonucleotide reductase has led to several proposals for therapeutic application. 

---