Ribonucleotide reductases: Divergent evolution of an ancient enzyme

Eduard Torrents, Patrick Aloy, Isidre Gibert, Francisco Rodríguez-Trelles

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76 Citations (Scopus)


Ribonucleotide reductases (RNRs) are uniquely responsible for converting nucleotides to deoxynucleotides in all dividing cells. The three known classes of RNRs operate through a free radical mechanism but differ in the way in which the protein radical is generated. Class I enzymes depend on oxygen for radical generation, class II uses adenosylcobalamin, and the anaerobic class III requires S-adenosylmethionine and an iron-sulfur cluster. Despite their metabolic prominence, the evolutionary origin and relationships between these enzymes remain elusive. This gap in RNR knowledge can, to a major extent, be attributed to the fact that different RNR classes exhibit greatly diverged polypeptide chains, rendering homology assessments inconclusive. Evolutionary studies of RNRs conducted until now have focused on comparison of the amino acid sequence of the proteins, without considering how they fold into space. The present study is an attempt to understand the evolutionary history of RNRs taking into account their three-dimensional structure. We first infer the structural alignment by superposing the equivalent stretches of the three-dimensional structures of representatives of each family. We then use the structural alignment to guide the alignment of all publicly available RNR sequences. Our results support the hypothesis that the three RNR classes diverged from a common ancestor currently represented by the anaerobic class III. Also, lateral transfer appears to have played a significant role in the evolution of this protein family.
Original languageEnglish
Pages (from-to)138-152
JournalJournal of Molecular Evolution
Issue number2
Publication statusPublished - 17 Jul 2002


  • Lateral transfer
  • nrd
  • Phylogeny
  • Pyruvate formate lyase
  • Ribonucleotide reductase (RNR)
  • RNR evolution
  • Structural alignment


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