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The alternative aerobic ribonucleotide reductase of Escherichia coli, NrdEF, is a manganese-dependent enzyme that enables cell replication during periods of iron starvation.
Mol Microbiol. 2011 Apr; 80(2):319-34
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25 Feb 2011
DOI: 10.3410/f.8642957.9139065
Bacteria employ various strategies to cope with iron deprivation. This paper describes yet another such mechanism. The class Ia ribonucleotide reductase (NrdAB) is essential to Escherichia coli under aerobic conditions, but only in the absence of exogenous deoxyribonucleotides.
However, this enzyme is...Continue reading
However, this enzyme is...Continue reading
Bacteria employ various strategies to cope with iron deprivation. This paper describes yet another such mechanism. The class Ia ribonucleotide reductase (NrdAB) is essential to Escherichia coli under aerobic conditions, but only in the absence of exogenous deoxyribonucleotides.
However, this enzyme is iron-dependent, suggesting that E. coli would be unable to manufacture deoxyribonucleotides under aerobic iron restriction. It turns out that this is not the case. The mysterious class Ib enzyme (NrdEF) takes over when iron is limited – but it can only do so if manganese is available. Appropriately, the genes encoding NrdEF and Mn2+ uptake are induced by iron starvation, and the NrdEF enzyme contains a di-Mn centre, rather than a di-Fe centre, as found in NrdAB. Thus, the purpose of NrdEF is explained (substitution for NrdAB under iron restriction) and a new means to resist iron restriction is revealed.
However, this enzyme is iron-dependent, suggesting that E. coli would be unable to manufacture deoxyribonucleotides under aerobic iron restriction. It turns out that this is not the case. The mysterious class Ib enzyme (NrdEF) takes over when iron is limited – but it can only do so if manganese is available. Appropriately, the genes encoding NrdEF and Mn2+ uptake are induced by iron starvation, and the NrdEF enzyme contains a di-Mn centre, rather than a di-Fe centre, as found in NrdAB. Thus, the purpose of NrdEF is explained (substitution for NrdAB under iron restriction) and a new means to resist iron restriction is revealed.
Disclosures
None declared
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Andrews S: F1000Prime Recommendation of [Martin JE and Imlay JA, Mol Microbiol 2011, 80(2):319-34]. In F1000Prime, 25 Feb 2011; DOI: 10.3410/f.8642957.9139065. F1000Prime.com/8642957#eval9139065
02 Jun 2011
New Finding
DOI: 10.3410/f.8642957.11871060
This study helps answer the long-standing question of why Escherichia coli possess a class Ib ribonucleotide reductase, NrdEF, in addition to the class Ia enzyme, NrdAB. While the diferric NrdAB is employed by cells under normal aerobic growth, the in vivo function of NrdEF was found to require manganese...Continue reading
This study helps answer the long-standing question of why Escherichia coli possess a class Ib ribonucleotide reductase, NrdEF, in addition to the class Ia enzyme, NrdAB. While the diferric NrdAB is employed by cells under normal aerobic growth, the in vivo function of NrdEF was found to require manganese and is utilized by the bacteria during iron-depleted conditions to provide deoxyribonucleotides for DNA synthesis.
Based on previous studies, it was hypothesized that a manganese-activated NrdEF, which is not functional during normal aerobic growth, might be utilized under oxidative stress conditions due to the inactivation of the iron-dependent NrdAB. However, in vivo experiments found that while persistent hydrogen peroxide does induce NrdEF expression, NrdAB remains functional. Increased expression of NrdEF under these conditions was traced back to decreased iron levels via derepression by Fur and activation by apo-IscR. Further genetic experiments coupled with whole-cell EPR analyses found that functional NrdEF requires manganese and is both necessary and sufficient for ribonucleotide reductase activity under iron-deficient conditions. The in vivo studies from Martin and Imlay complement the recent biochemical findings from Cotruvo and Stubbe {1}, which show that active dimanganese NrdEF is isolated from iron-starved E. coli. Since several pathogens appear to solely rely upon class Ib NrdEF homologs during aerobic growth, these findings suggest that a manganese-dependent NrdEF may provide a strategy by which bacteria combat the iron sequestration employed by the host as a defense mechanism.
References:
{1} Cotruvo and Stubbe, Biochemistry 2011, 50:1672-81 [PMID:21250660].
Based on previous studies, it was hypothesized that a manganese-activated NrdEF, which is not functional during normal aerobic growth, might be utilized under oxidative stress conditions due to the inactivation of the iron-dependent NrdAB. However, in vivo experiments found that while persistent hydrogen peroxide does induce NrdEF expression, NrdAB remains functional. Increased expression of NrdEF under these conditions was traced back to decreased iron levels via derepression by Fur and activation by apo-IscR. Further genetic experiments coupled with whole-cell EPR analyses found that functional NrdEF requires manganese and is both necessary and sufficient for ribonucleotide reductase activity under iron-deficient conditions. The in vivo studies from Martin and Imlay complement the recent biochemical findings from Cotruvo and Stubbe {1}, which show that active dimanganese NrdEF is isolated from iron-starved E. coli. Since several pathogens appear to solely rely upon class Ib NrdEF homologs during aerobic growth, these findings suggest that a manganese-dependent NrdEF may provide a strategy by which bacteria combat the iron sequestration employed by the host as a defense mechanism.
References:
{1} Cotruvo and Stubbe, Biochemistry 2011, 50:1672-81 [PMID:21250660].
Disclosures
None declared
Matthews R and Hondorp E: F1000Prime Recommendation of [Martin JE and Imlay JA, Mol Microbiol 2011, 80(2):319-34]. In F1000Prime, 02 Jun 2011; DOI: 10.3410/f.8642957.11871060. F1000Prime.com/8642957#eval11871060
F1000Prime Recommendations, Dissents and Comments for [Martin JE and Imlay JA, Mol Microbiol 2011, 80(2):319-34]. In F1000Prime, 19 May 2013; F1000Prime.com/8642957
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The genome of Escherichia coli encodes two class I ribonucleotide reductases. The first, NrdAB, is a well-studied iron-dependent enzyme that is essential for aerobic growth. The second, NrdEF, is not functional under routine conditions, and its role is obscure. Recent studies demonstrated that NrdEF can be activated in vitro by manganese as well as iron. Since iron enzymes are potential targets for hydrogen peroxide, and since the nrdHIEF operon is induced during H(2) O(2) stress, we hypothesized that H(2) O(2) might inactivate NrdAB and that NrdEF might be induced to compensate. This idea was tested using E. coli mutants that are chronically stressed by H(2) O(2) . Contrary to expectation, NrdAB remained active. Its resistance to H(2) O(2) depended upon YfaE, which helps to activate NrdB. The induction of NrdEF during H(2) O(2) stress was mediated by the inactivation of Fur, an iron-dependent repressor. This regulatory arrangement implied that NrdEF has a physiological role during periods of iron starvation. Indeed, NrdEF supported cell replication in iron-depleted cells. Iron bound to NrdF when it was expressed in iron-rich cells, but NrdEF was functional only in cells that were both iron-depleted and manganese-rich. Thus NrdEF supports DNA replication when iron is unavailable to activate the housekeeping NrdAB enzyme.
© 2011 Blackwell Publishing Ltd.
DOI: 10.1111/j.1365-2958.2011.07593.x
PMID: 21338418
