1] Thiols in redox mechanism of ribonucleotide reductase

Abstract

Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to the corresponding deoxyribonucleotides, thereby providing cells with the necessary building blocks for DNA synthesis and repair. Redox active cysteines, thiyl radicals, and thiol proteins are central to catalysis by all three classes of RNR. All classes are related via divergent evolution; class I and II have striking overall sequence similarities, and the known three-dimensional structures of class I and III show structural similarity. The arrangement of catalytically essential side chains in active sites has been preserved among class I RNR, class III RNR, and pyruvate formate-lyase. In class I RNRs, the stable tyrosyl radical is stored in one component (called protein R2) of the holoenzyme. In class II RNRs, catalysis requires that the AdoCbl cofactor is cleaved homolytically to generate a transient 5'-deoxyadenosyl radical. In class III RNRs, the stable radical is generated by a separate activating enzyme (NrdG) and is stored in the reductase proper (NrdD) at a glycyl moiety some distance from the active site. The overall mechanism for reduction of ribonucleotides can be described both as similar and as distinct among the three classes of RNR. This chapter emphasizes both these aspects, outlining the unifying steps of the mechanism.