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A ribonucleotide reductase from Clostridium botulinum reveals distinct evolutionary pathways to regulation via the overall activity site
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2020 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 295, no 46, p. 15576-15587Article in journal (Refereed) Published
Abstract [en]

Ribonucleotide reductase (RNR) is a central enzyme for the synthesis of DNA building blocks. Most aerobic organisms, including nearly all eukaryotes, have class I RNRs consisting of R1 and R2 subunits. The catalytic R1 subunit contains an overall activity site that can allosterically turn the enzyme on or off by the binding of ATP or dATP, respectively. The mechanism behind the ability to turn the enzyme off via the R1 subunit involves the formation of different types of R1 oligomers in most studied species and R1-R2 octamers in Escherichia coli. To better understand the distribution of different oligomerization mechanisms, we characterized the enzyme from Clostridium botulinum, which belongs to a subclass of class I RNRs not studied before. The recombinantly expressed enzyme was analyzed by size-exclusion chromatography, gas-phase electrophoretic mobility macromolecular analysis, EM, X-ray crystallography, and enzyme assays. Interestingly, it shares the ability of the E. coli RNR to form inhibited R1-R2 octamers in the presence of dATP but, unlike the E. coli enzyme, cannot be turned off by combinations of ATP and dGTP/dTTP. A phylogenetic analysis of class I RNRs suggests that activity regulation is not ancestral but was gained after the first subclasses diverged and that RNR subclasses with inhibition mechanisms involving R1 oligomerization belong to a clade separated from the two subclasses forming R1-R2 octamers. These results give further insight into activity regulation in class I RNRs as an evolutionarily dynamic process.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2020. Vol. 295, no 46, p. 15576-15587
Keywords [en]
Clostridium botulinum, ribonucleotide reductase, allosteric regulation, overall activity regulation, inhibition mechanism, a-site, oligomerization, phylogenetics, evolution, structure–, function
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-178061DOI: 10.1074/jbc.RA120.014895ISI: 000594361600013PubMedID: 32883811Scopus ID: 2-s2.0-85096203090OAI: oai:DiVA.org:umu-178061DiVA, id: diva2:1513450
Funder
Swedish Research Council, 2019-01242Swedish Research Council, 2018-03406Swedish Research Council, 2019-01400Swedish Cancer Society, 2017/716Swedish Cancer Society, 2018/820Available from: 2020-12-30 Created: 2020-12-30 Last updated: 2023-03-24Bibliographically approved

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Jonna, Venkateswara RaoCarlson, Lars-AndersHofer, Anders

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Jonna, Venkateswara RaoCarlson, Lars-AndersHofer, Anders
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Department of Medical Biochemistry and BiophysicsWallenberg Centre for Molecular Medicine at Umeå University (WCMM)
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Journal of Biological Chemistry
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