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DNA building blocks: keeping control of manufacture

På svenska

Author

  • Anders Hofer
  • Mikael Crona
  • Derek Logan
  • Britt-Marie Sjoberg

Summary, in English

Ribonucleotide reductase (RNR) is the only source for de novo production of the four deoxyribonucleoside triphosphate (dNTP) building blocks needed for DNA synthesis and repair. It is crucial that these dNTP pools are carefully balanced, since mutation rates increase when dNTP levels are either unbalanced or elevated. RNR is the major player in this homeostasis, and with its four different substrates, four different allosteric effectors and two different effector binding sites, it has one of the most sophisticated allosteric regulations known today. In the past few years, the structures of RNRs from several bacteria, yeast and man have been determined in the presence of allosteric effectors and substrates, revealing new information about the mechanisms behind the allosteric regulation. A common theme for all studied RNRs is a flexible loop that mediates modulatory effects from the allosteric specificity site (s-site) to the catalytic site for discrimination between the four substrates. Much less is known about the allosteric activity site (a-site), which functions as an on-off switch for the enzyme's overall activity by binding ATP (activator) or dATP (inhibitor). The two nucleotides induce formation of different enzyme oligomers, and a recent structure of a dATP-inhibited alpha(6)beta(2) complex from yeast suggested how its subunits interacted non-productively. Interestingly, the oligomers formed and the details of their allosteric regulation differ between eukaryotes and Escherichia coli. Nevertheless, these differences serve a common purpose in an essential enzyme whose allosteric regulation might date back to the era when the molecular mechanisms behind the central dogma evolved.

Publishing year

2012

Language

English

Pages

50-63

Publication/Series

Critical Reviews in Biochemistry and Molecular Biology

Volume

47

Issue

1

Document type

Journal article review

Publisher

CRC Press

Topic

  • Biological Sciences

Keywords

  • Ribonucleotide reductase
  • RNR
  • allosteric regulation
  • specificity site
  • activity site
  • ATP cone
  • dATP inhibition

Status

Published

ISBN/ISSN/Other

  • ISSN: 1040-9238