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J. Biol. Chem., Vol. 281, Issue 38, 27705-27711, September 22, 2006

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Enzymatically Active Mammalian Ribonucleotide Reductase Exists Primarily as an ₆₂ Octamer^*

From the Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden

Ribonucleotide reductase synthesizes deoxyribonucleotides, which are essential building blocks for DNA synthesis. The mammalian ribonucleotide reductase is described as an ₂₂ complex consisting of R1 () and R2 () proteins. ATP stimulates and dATP inhibits enzyme activity by binding to an allosteric site called the activity site on the R1 protein. Despite the opposite effects by ATP and dATP on enzyme activity, both nucleotides induce formation of R1 oligomers. By using a new technique termed Gas-phase Electrophoretic-Mobility Macromolecule Analysis (GEMMA), we have found that the ATP/dATP-induced R1 oligomers have a defined size (hexamers) and can interact with the R2 dimer to form an enzymatically active protein complex (₆₂). The newly discovered ₆₂ complex can either be in an active or an inhibited state depending on whether ATP or dATP is bound. Our results suggest that this protein complex is the major form of ribonucleotide reductase at physiological levels of R1-R2 protein and nucleotides.

Received for publication, June 9, 2006 , and in revised form, July 19, 2006.

^* This work was supported by the Swedish Research Council (521-2003-3745) and the Magnus Bergvall Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 46-90-7867840; Fax: 46-90-7869795; E-mail: anders.hofer{at}medchem.umu.se.

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