Structure, function, and mechanism of ribonucleotide reductases

Matthias Kolberg, Kari R. Strand, Pål Graff, K. Kristoffer Andersson

Research output: Contribution to journalReview article

281 Citations (Scopus)

Abstract

Ribonucleotide reductase (RNR) is the enzyme responsible for the conversion of ribonucleotides to 2′-deoxyribonucleotides and thereby provides the precursors needed for both synthesis and repair of DNA. In the recent years, many new crystal structures have been obtained of the protein subunits of all three classes of RNR. This review will focus upon recent structural and spectroscopic studies, which have offered deeper insight to the mechanistic properties as well as evolutionary relationship and diversity among the different classes of RNR. Although the three different classes of RNR enzymes depend on different metal cofactors for the catalytic activity, all three classes have a conserved cysteine residue at the active site located on the tip of a protein loop in the centre of an α/β-barrel structural motif. This cysteine residue is believed to be converted into a thiyl radical that initiates the substrate turnover in all three classes of RNR. The functional and structural similarities suggest that the present-day RNRs have all evolved from a common ancestral reductase. Nevertheless, the different cofactors found in the three classes of RNR make the RNR proteins into interesting model systems for quite diverse protein families, such as diiron-oxygen proteins, cobalamin-dependent proteins, and SAM-dependent iron-sulfur proteins. There are also significant variations within each of the three classes of RNR. With new structures available of the R2 protein of class I RNR, we have made a comparison of the diiron centres in R2 from mouse and Escherichia coli. The R2 protein shows dynamic carboxylate, radical, and water shifts in different redox forms, and new radical forms are different from non-radical forms. In mouse R2, the binding of iron(II) or cobalt(II) to the four metal sites shows high cooperativity. A unique situation is found in RNR from baker's yeast, which is made up of heterodimers, in contrast to homodimers, which is the normal case for class I RNR. Since the reduction of ribonucleotides is the rate-limiting step of DNA synthesis, RNR is an important target for cell growth control, and the recent finding of a p53-induced isoform of the R2 protein in mammalian cells has increased the interest for the role of RNR during the different phases of the cell cycle.

Original languageEnglish (US)
Pages (from-to)1-34
Number of pages34
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1699
Issue number1-2
DOIs
StatePublished - Jun 1 2004

Fingerprint

Ribonucleotide Reductases
Proteins
Ribonucleotides
Cysteine
Metals
Cells
Deoxyribonucleotides
Iron-Sulfur Proteins
DNA
Protein Subunits
Cell growth
Enzymes
Vitamin B 12
Cobalt
DNA Repair
Yeast
Escherichia coli
Oxidation-Reduction
Saccharomyces cerevisiae

Keywords

  • Function
  • Ribonucleotide reductase
  • Structure

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Structure, function, and mechanism of ribonucleotide reductases. / Kolberg, Matthias; Strand, Kari R.; Graff, Pål; Andersson, K. Kristoffer.

In: Biochimica et Biophysica Acta - Proteins and Proteomics, Vol. 1699, No. 1-2, 01.06.2004, p. 1-34.

Research output: Contribution to journalReview article

Kolberg, Matthias ; Strand, Kari R. ; Graff, Pål ; Andersson, K. Kristoffer. / Structure, function, and mechanism of ribonucleotide reductases. In: Biochimica et Biophysica Acta - Proteins and Proteomics. 2004 ; Vol. 1699, No. 1-2. pp. 1-34.
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