Ribonucleotide reductases: essential enzymes for bacterial life

Abstract

Ribonucleotide reductase (RNR) is a key enzyme that mediates the synthesis of deoxyribonucleotides, the DNA precursors, for DNA synthesis in every living cell. This enzyme converts ribonucleotides to deoxyribonucleotides, the building blocks for DNA replication, and repair. Clearly, RNR enzymes have contributed to the appearance of genetic material that exists today, being essential for the evolution of all organisms on Earth. The strict control of RNR activity and dNTP pool sizes is important, as pool imbalances increase mutation rates, replication anomalies, and genome instability. Thus, RNR activity should be finely regulated allosterically and at the transcriptional level. In this review we examine the distribution, the evolution, and the genetic regulation of bacterial RNRs. Moreover, this enzyme can be considered an ideal target for anti-proliferative compounds designed to inhibit cell replication in eukaryotic cells (cancer cells), parasites, viruses, and bacteria.

Keywords: DNA synthesis; NrdR; anaerobiosis; evolution; gene regulation; ribonucleotide reductase; transcriptional regulation.

Figure 1

The reduction of ribonucleotides to deoxyribonucleotides by RNR. Three different RNR classes (I, II, and III) have been described for this enzyme family. RNR is important for evolution, as this enzyme played an important role during the transition from an RNA to a DNA world. RNR enzymes catalyze the reduction of the ribose C2′-OH to C2′-H.

Figure 2

Allosteric regulation of RNR. Model showing the allosteric regulation of class Ia RNRs. The binding of ATP at the substrate specificity site activates the enzyme, promoting the reduction of CDP and UDP to dCDP and dUDP, respectively. Once formed, dTTP promotes the reduction of GDP to dGDP, which in turn induces the reduction of ADP to dADP. A high dATP concentration inhibits the overall activity of this enzyme through binding to the allosteric activity site. Green plus symbols indicate stimulation of RNR reduction, and red minus symbols indicate inhibition.

Figure 3

RNRs as survival markers under aerobic or anaerobic environments. RNR classes can be activated under different environmental conditions in which one organism survives depending on the oxygen availability (aerobic, anaerobic, and in the interface). The distribution of each RNR class in the three domains of life (eubacteria, archaea, and eukaryotes) is shown. The thicker line represents higher RNR class occurrence, and the thinner line corresponds to the occurrence in only a few organisms.

Figure 4

nrdR operon organization and hypothetical mechanism of transcription regulation by NrdR. (A) Structure of the nrdR operon and functional protein domains for the NrdR transcriptional regulator. (B) Hypothetical mechanism for the transcriptional regulation of the nrd gene through NrdR. Depending on which nucleotide is bound and the oligomerization state of the NrdR, this transcription factor can modulate the expression of the nrd genes through binding to the specific NrdR-box.

Figure 5

The mode of action of different RNR inhibitors.