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Iron homeostasis and management of oxidative stress response in bacteria

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 Metallomics
1 1
Cite this: DOI: 10.1039/c1mt00022e

5
www.rsc.org/metallomics MINIREVIEW 5

Q1 Iron homeostasis and management of oxidative stress response

in bacteria
10 10
Pierre Cornelis,*a Qing Wei,a Simon C. Andrewsb and Tiffany Vinckxa
Received 21st February 2011, Accepted 14th April 2011
DOI: 10.1039/c1mt00022e
15 15
Iron is both an essential nutrient for the growth of microorganisms, as well as a dangerous metal
due to its capacity to generate reactive oxygen species (ROS) via the Fenton reaction. For these
reasons, bacteria must tightly control the uptake and storage of iron in a manner that restricts the
build-up of ROS. Therefore, it is not surprising to find that the control of iron homeostasis and
20 responses to oxidative stress are coordinated. The mechanisms concerned with these processes, 20
and the interactions involved, are the subject of this review.

Introduction Fe3+ with the glycoproteins, transferrin and lactoferrin.1,2

25 For the vast majority of microorganisms iron is an essential
element that is not easily available under aerobic conditions,
due to the poor solubility of the oxidized Fe3+ form.1 For this
reason, environmental microorganisms exercising aerobic life-
styles are frequently confronted with shortages of bioavailable
30 iron. For pathogens, the iron-restriction problem is even more
extreme since the host actively limits iron availability by
sequestering it within intracellular proteins such as hemoglo-
bin, cytochromes or ferritins, or by chelating extracellular
Iron is essential for microorganisms due to its involvement
in multiple metabolic processes including respiration ([Fe–S]- 25
containing ferredoxins, heme-containing cytochromes) and
key enzymatic reactions (e.g. [Fe–S] proteins, such as fumarase
and aconitase of the TCA cycle). However, iron can also
present a hazard to organisms because of the Fe2+-triggered
Fenton/Haber-Weiss reaction which produces harmful reac- 30
tive oxygen species (ROS) such as superoxide (O2), hydrogen
peroxide (H2O2) and the highly destructive hydroxyl radical
( OH).

35 a Fe3+ +  O2 - Fe2+ + O2 35

Microbial Interactions, Department of Molecular and Cellular
Interactions, VIB and Vrije Universiteit Brussel, Pleinlaan 2, 1050
Brussels, Belgium. E-mail: pcornel@vub.ac.be
b
School of Biological Sciences, Whiteknights, University of Reading, Fe2+ + H2O2 - Fe3+ + OH +  OH
Reading, UK RG6 6AJ
40 40

Pierre Cornelis is Professor of Qing Wei is a Chinese student

General and Molecular Mi-
crobiology at the Vrije Univer-
siteit Brussel (VUB) and a
45 Senior Group Leader at the
Flemish Institute of Biotech-
nology (VIB). He obtained
his PhD in 1975 and has been
at the VUB since 1988. He
50 organized the Pseudomonas
meeting in Brussels in 2011.
His research focuses on iron
uptake (siderophore recep-
tors, regulation) and homeos-
Pierre Cornelis tasis in P. aeruginosa. He
55 recently investigated the role
of the regulator OxyR in iron management. He was editor of the
book Pseudomonas Genomics and Molecular Biology. He is co-
editor of the recently published book ‘Iron Uptake and Home-
ostasis in Microorganisms’.
doing his PhD in the labora-
tory of Pierre Cornelis on iron
homeostasis and oxidative
stress in P. aeruginosa. He 45
investigates the role of the
OxyR regulator in the man-
agement of iron uptake and
in response to stress. Last
year, he was awarded a FEMS 50
fellowship to work in the La-
boratory of Prof. Susanne
Haüssler in Braunschweig.
Qing Wei
55

This journal is 
c The Royal Society of Chemistry 2011 Metallomics, 2011, ]]], 1–10 | 1
 1 Net reaction:  O2 + H2O2 -  OH + OH + O2
These ROS can cause damage to [Fe–S] clusters, protein
carbonylation, Cys/Met-residue oxidation, membrane lipid
5 peroxidation, and DNA damage.3–6 ROS are ‘accidentally’
generated by aerobes via incomplete reduction of O2 during
respiration and through flavin-mediated reductive processes.7
ROS are also produced deliberately during competition be-
tween organisms as the result of redox-cycling antibiotics, as
10 generated by plants and microbes. Phagocytic mammalian
cells (e.g. macrophages) intentionally produce such reactive
oxygen species (as well as NOS, reactive nitrogen species) in
order to attack and destroy engulfed microorganisms. This
involves the so-called ‘oxidative burst’ response which is an
15 important component of innate immune defense. As a con-
sequence of such natural exposure to ROS, many bacteria,
particularly aerobes and pathogens, have developed mechan-
isms to resist redox stress assault. The main strategy employed
is production of enzymes that degrade ROS species (and their
20 precursors) to maintain stress levels within the range of
tolerance. Such ROS degrading enzymes include superoxide
dismutases, catalases, alkylhydroperoxidases, superoxide re-
ductases and peroxidases, and some of these, ironically, are Fe
co-factored (e.g. mononuclear Fe for some superoxide dismu-
25 tases and superoxide reductase, and heme iron for cata-
lases).8–11 Since iron is a major contributor to redox stress
(and is also required by some ROS-degrading enzymes), it is
no surprise to find that there is significant regulatory cross-talk
between the iron homeostasis and oxidative-stress resistance
30 networks. It is this bacterial iron-ROS interface that is the
focus of this review. In particular, we aim to highlight some of
the key recent developments that have arisen since the superb
review of Touati in 200012 and will complement the very recent
review of Faulkner and Helmann.13
35
Simon C. Andrews is Profes-
40 sor of Molecular Microbiol-
ogy at the School of
Biological Sciences in the Uni-
versity of Reading, UK. Prof.
Andrews obtained his PhD in
Biochemistry at the University
45 of Sheffield in 1982 under the
supervision of Prof. Pauline
Harrison, and continued at
Sheffield as a Research Assis-
tant working with Prof. John
50 Guest in Microbiology and
then progressing to a BBSRC
Simon C. Andrews Advanced Fellowship in the
Department of Mol. Biol. &
Biotechnol. (Sheffield). In 1998 he moved to Reading as Reader
in Microbial Biochemistry, and was promoted to a personal
55 Chair in 2008. His research focuses on iron homeostasis (reg-
ulation, storage, transport) in bacteria. Prof. Andrews is cur-
rently head of the section of Biomedical Sciences (Reading). He
is co-editor of the recently published book ‘Iron Uptake and
Homeostasis in Microorganisms’.
2 | Metallomics, 2011, ]]], 1–10
Siderophore-mediated iron uptake in bacteria 1
In the presence of oxygen at physiological pH, iron is oxidized
(Fe3+) and is highly insoluble due to the formation of poorly
soluble iron hydroxides. This is why bacteria have to produce 5
strong extracellular Fe3+chelators, termed siderophores.1,14,15
The general mechanism of siderophore-mediated high-affinity
iron uptake by Gram-positive and Gram-negative bacteria is
depicted in Fig. 1. Gram-positive bacteria have only one
membrane and so require only one receptor together with a 10
coupled ABC-type permease, which are both membrane-asso-
ciated. Gram-negative bacteria have two membranes so re-
quire a receptor in the outer membrane (ferri-siderophores are
too large to pass through the porins of outer-membrane), an
intermediate ferrisiderophore-binding protein in the periplasm 15
as well as an ABC-type permease.1 Once in the cytoplasm, the
ferrisiderophore is either degraded by an esterase, as in the
case of enterobactin, or there is a reductive process leading to
the release of Fe2+ leaving the iron chelator (apo-siderophore)
intact, allowing re-cycling.1 Little is known about these ferri- 20
siderophore reductases, but it seems that some are proteins
containing a [Fe–S] center while others are NADP(H)-depen-
dent flavoproteins.16–18 The reduction step is quite important
because mutants in currently identified ferric reductase genes
show poor growth under iron-limiting conditions and in- 25
creased sensitivity to oxidative stress, probably because Fe is
needed for heme-containing catalases, and for the activity of
Fe-containing superoxide dismutase (Sod) enzymes.17
Heme-mediated iron uptake in bacteria 30
Another important source of iron for bacteria is heme, which
is obtained from the hosts they colonize.19 Heme must first be
extracted from hemoproteins such as hemoglobin or hemo-
pexin. It is not found in the unbound form because free heme 35
is both toxic as well as highly hydrophobic causing it to
Tiffany Vinckx did her PhD in
the laboratory of Pierre Cor- 40
nelis and presented her thesis
at the end of 2009. She was the
one who discovered the impor-
tance of OxyR for the man-
agement of low or high iron
stress by P. aeruginosa. 45
50
Tiffany Vinckx
55
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c The Royal Society of Chemistry 2011
 1 1

5 5

10 10

15 15

20 20

Fig. 1 Mechanisms of siderophore-mediated iron uptake in Gram-positive (A) and in Gram-negative bacteria (B): Fe 3+ is chelated by a secreted
siderophore and the complex binds a receptor which transfers the ferrisiderophore to a transporter either directly (in the case of Gram + bacteria)
or via a periplasmic binding protein (in the case of Gram bacteria). In Gram-negative bacteria the energy for the transport of the ferrisiderophore
25 to the periplasm after binding to the gated porin receptor is transmitted by the inner membrane TonB protein assisted by ExbB and ExbD. Once in 25
the cytoplasm the iron is removed by a reductive process or by the action of an esterase. Reactive oxygen species could interfere with the reductive
process when the reductase contains [Fe–S] cluster(s).

associate with membranes where it promotes non-enzymatic
redox reactions.20 Two types of pathways for the uptake of
30
heme have been described, one based on the release of extra-
cellular hemophore proteins that scavenge heme while the
other pathway involves receptors that directly bind hemopro-
teins and extract heme19,21 (Fig. 2). Once inside the cytoplasm,
heme is either broken down to biliverdin and CO via a heme
35
oxygenase or, as described recently, heme can be de-ferrated
leaving the tetrapyrrole ring intact19,22 (Fig. 2). As already
30
mentioned, free heme is toxic, which is why some proteins bind
heme as chaperones to prevent oxidative damage.20,23
35

40 40

45 45

50 50

55 Fig. 2 Mechanisms of heme uptake in Gram-positive (A) and in Gram-negative bacteria (B): in Gram-positive bacteria the hemoprotein is 55
recognized by a receptor and the extracted heme is shuttled via NEAT (Near [iron] Transporters) proteins to a transporter; in Gram negative
bacteria the hemoprotein is either bound directly by a gated porin receptor at the outer membrane or heme is first bound to an extracellular
hemophore protein. Transport of heme to a periplasmic binding protein is TonB-dependent as in the case of ferrisiderophores. Once in the
cytoplasm heme is either degraded by a heme oxygenase to biliverdin, CO and iron or heme is de-ferrated to give protoporphyrin IX (PPX).

This journal is 
c The Royal Society of Chemistry 2011 Metallomics, 2011, ]]], 1–10 | 3
 1 Iron storage in bacteria
In many bacteria, including aerotolerant anaerobes, iron is
stored in three types of protein: ferritins, bacterioferritins, and
5 the DNA-binding protein Dps.24–27 Their function is two-fold:
on the one hand they provide a source of iron that can be
utilized when this metal becomes scarce, on the other hand, by
sequestering iron they protect the cell from the ROS produced
via the Fenton reaction. This is particularly the case for Dps
Q3
10 (DNA-binding proteins from starved cells), which belongs to
the ferritin family of proteins but contains just 12 subunits
rather than 24, as found in larger ferritins and bacterioferri-
tins.28 Dps proteins protect DNA against Fenton-mediated
oxidative stress since they use H2O2 to catalyze the oxidation
15 of Fe2+ at ferroxidase centers generating water rather than
ROS.28,29 We will see later that these genes are controlled both
by iron availability and oxidative stress.
Enzymes involved in the detoxification of ROS
20
The superoxide anion (O2) is dangerous because it can
damage [Fe–S] centers in proteins resulting in their inactiva-
tion and in the release of free Fe in the cell.7 One or more
superoxide dismutase(s) (Sod) is/are part of a first line defense
25 of nearly all aerobes. These enzymes catalyze the dismutation
of O2 to H2O2 and O2. Sods contain a Mn-, Fe-, Cu/Zn- or
Ni-based cofactor. For example, E. coli is equipped with three
Sods: one cytosolic Fe-Sod (SodB), one cytosolic Mn-Sod
(SodA), and a periplasmic Cu/Zn-Sod (SodC).30 H2O2 is not
30 a radical, but nevertheless it can oxidize certain biomolecules,
including [Fe–S] clusters, and cysteine (Cys) and methionine
(Met) residues, which are often present in active sites of
proteins. Among ROS, H2O2 is the longest-lived and it is the
product of the Sod-catalyzed dismutation of O2, diffusing
35 freely through membranes. In addition, cells are faced with
various exogenous sources of H2O2, such as that provided by
the phagosomal oxidative burst upon infection of mamma-
lians by bacteria.6,31 Catalases and peroxidases represent a
second line of defence and inactivate H2O232 according to the
40 following reaction schemes:
2H2O2 - 2H2O + O2 (catalase)
ROOR 0 + electron donor (2e) + 2H+ - ROH + R 0 OH
45 (peroxidase)
In addition to catalases and peroxidases, non-heme, cysteine-
based enzymes catalyze the reduction of alkyl hydroperoxides.
These are termed peroxiredoxins (Prxs) or alkyl hydroperoxide
reductases (Ahps) and they act as broad-specificity peroxi-
50
dases, reducing H2O2 and small alkyl hydroperoxides.32
Regulation of iron uptake and storage in bacteria:
the Fur paradigm
55
As indicated earlier, tight control of iron uptake is crucial for
microorganisms in order to avoid the accumulation of poten-
tially dangerous free iron in the cell which could trigger the
Fenton reaction.3–6
4 | Metallomics, 2011, ]]], 1–10
The ferric uptake regulator (Fur) is a conserved protein in 1
many different bacteria, both Gram-positive and Gram-nega-
tive, which operates primarily as a repressor of iron-uptake
genes (e.g. those involved in siderophore biosynthesis or in
transport across the membrane). Fur repression is generally 5
achieved when the homodimeric protein is associated to its co-
repressor, Fe2+.33–35 Fur binds one structural Zn2+ and one
regulatory Fe2+ per monomer. It often acts as a global
regulator, either directly repressing the transcription of its
target genes or indirectly controlling their expression via 10
secondary regulators (extracytoplasmic s factors [ECFs],
AraC regulators, two-component sensors, small RNAs). For
instance, in P. aeruginosa Fur-Fe2+ represses the expression of
11 ECF s factors and two other regulators.36 The Fur-Fe2+
complex generally controls expression by binding to a con- 15
sensus sequence (the Iron or Fur box) that overlaps the
promoters of genes under its direct control.34,36,37 Binding to
the Fur box blocks access of RNA polymerase to the promoter
thus inhibiting transcription of the downstream gene(s).36 In
this way, down-regulation of iron uptake components is 20
achieved when cellular iron levels are high. However, Fur is
not the only answer to the iron-control problem in bacteria, as
in some cases very different regulators are used in place of
Fur.35 For instance, high-GC Gram positive bacteria tend to
use DtxR-like proteins to control iron-dependent gene expres- 25
sion (DtxR in Corynebacterium species38–40 and IdeR in
Mycobacterium tuberculosis41–44). The DtxR proteins operate
in a fashion similar to that of Fur proteins, although they are
phylogenetically unrelated.
In Rhizobiales, the story is different yet again. A protein 30
very similar to Fur is present but surprisingly is not involved in
the regulation of iron homeostasis. Instead, this Fur-like
protein responds to manganese (and so is designated ‘Mur’)
and its role appears limited to the control of manganese
uptake via the MntH.45–47 The iron homeostasis regulatory 35
function in Rhizobiales is fulfilled by two other regulators,
RirA (rhizobial iron regulator) and Irr (iron response regula-
tor).48,49 RirA is a member of the Rrf2 family of transcription
regulators (Pfam, PF001022) that include the [Fe–S] cluster-
sensing IsrR repressor and the NO-responsive NsrR activator. 40
RirA functions as a transcriptional repressor of iron uptake
via siderophores in Rhizobium leguminosarum and Sinorhizo-
bium meliloti.50–52 However, unlike Fur, RirA appears to
respond to [Fe–S]-cluster status rather than cellular free-iron
levels. The other rhizobial iron-regulatory protein, Irr, is a 45
distant member of the Fur family and so is quite distinct from
RirA. Irr was initially found to be involved mainly in the
regulation of heme biosynthesis, but it is now clear that it is
also a global regulator of iron homeostasis and metabolism in
many a-Proteobacteria. Unlike Fur, its regulatory activity is 50
not directly dependent on free-iron levels. Instead, its activity
depends on cellular heme/protoporphyrin status.49,53–56 When
iron levels are sufficient, Irr associates with ferrochelatase and
binds to heme which initiates Irr degradation. When iron is
low, heme production is reduced so Irr remains heme-free, and 55
ferrochelatase is present in the protoporphyrin-bound state
which triggers its dissociation from Irr. In this way, Irr
remains stable and free to control (it acts as both activator
and repressor) multiple genes involved in iron homeostasis.
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c The Royal Society of Chemistry 2011
 1 Thus in the rhizobia, iron control is exerted by monitoring
cellular heme levels and [Fe–S]-cluster status, rather than by
detection of the precursory cytosolic free-iron.
Although Fur generally behaves as a typical repressor, this
5 model has changed recently since in some bacteria, Fur has
been shown to positively regulate the expression of various
genes encoding iron proteins (e.g. bacterioferritin and the iron
co-factored superoxide dismutase, SodB1). This positive reg-
ulation is generally mediated indirectly by Fur-Fe repressed
10 small regulatory RNA molecules. In E. coli, the Fur-respon-
sive regulatory RNA is called RyhB. RyhB is able to hybridize
to targeted messages and so acts post-transcriptionally, in
conjunction with the Hfq protein (an RNA chaperone),
through the promotion of RNAse E-mediated degradation
15 of its target.58,59 RyhB can also stabilize target mRNAs and so
can act positively.60 In P. aeruginosa, the role of RyhB is taken
by two near-identical, co-transcribed, small, regulatory RNAs
(PrrF1 and PrrF2). In addition, a larger heme- and iron-
regulated transcript ‘PrrH’ is expressed from the prrF locus.
20 This molecule appears to mediate heme-dependent regulation
of target genes.61,62 RyhB is however not involved in the Fur-
mediated activation of the ferritin gene ftnA in E. coli, as
recently demonstrated.63 Upstream of the ftnA transcription
start site six binding sites for the histone-like protein H-NS are
25 found. Under conditions of iron limitation these sites are
occupied by H-NS, causing DNA looping which blocks the
access of RNA polymerase. However, when sufficient iron is
present in the cell, Fur-Fe2+ binds to an extended Fur box
which overlaps the H-NS binding region, thus displacing
30 H-NS and preventing DNA looping, which in turn allows
access of RNA polymerase.63 In some bacteria, such as
Helicobacter pylori and Neisseria meningitidis, Fur can work
directly as a positive regulator (or anti-repressor) to activate
the transcription of genes involved in virulence or in oxidative
35 stress response.64–68 In H. pylori, Fur can act as a repressor in
the apo-form for the sodB gene encoding the Fe co-factored
Sod.69 In M. tuberculosis, IdeR can also work as an activator
when its binding site is upstream of the promoter, as is the case
for the bacterioferritin and ferritin genes.70 Fig. 3 summarizes
40 how Fur-family proteins operate (Fig. 3a–c) and how the Irr
protein responds to the availability of heme (Fig. 3d).
Importance of the Fur family of regulators for the
resistance to oxidative stress
45
As might be expected, a mutation incapacitating global-iron
regulation can lead to accumulation of high levels of free-
cytosolic iron which in turn results in excessive iron-catalyzed
production of ROS;12 although it should be noted that in some
50 cases the global-iron regulator appears essential and so cannot
be inactivated (e.g. Fur in P. aeruginosa and IdeR in M.
tuberculosis43,57), possibly because of ensuing iron toxicity.
Furthermore, as already mentioned, Fur-Fe2+ can both in-
directly and directly activate the transcription of the genes
55 coding for iron proteins.1 This means that fur inactivation
simultaneously leads to unrestrained iron uptake and dimin-
ished incorporation of internalized iron into iron proteins. The
consequence of these two effects is amplification of ‘free’ iron
within the cytosol which greatly promotes Fenton chemistry
This journal is 
c The Royal Society of Chemistry 2011
and ROS buildup. A similar iron-toxicity effect may occur for 1
Mycobacterium smegmatis since ideR mutation caused raised
sensitivity towards hydrogen peroxide, and decreased levels of
the KatG and the Mn-Sod enzyme.42 In E. coli, it was shown
(surprisingly) that fur mutants have lower amounts of intra- 5
cellular iron but higher levels of reactive free Fe2+, due to the
reduced assimilation of iron into proteins, such as ferritin.71
The same phenomenon was observed in P. aeruginosa for
mutants with decreased Fur activity72 and in other bacteria
where fur mutations similarly lead to an increased sensitivity 10
to oxidative stress.73–75
In Agrobacterium tumefaciens and Sinorhizobium meliloti,
rirA mutants display a growth deficiency in iron-replete media,
due to enhanced accumulation of iron, and increased sensitiv-
ity to H2O2.50,76 15
Beyond the iron-responsive regulators described above,
another member of the Fur family plays a crucial role in
redox-stress management in some bacteria. This protein is
designated PerR (Peroxide regulator) and is found in Gram-
positive bacteria such as Bacillus subtilis, Clostridium acetobu- 20
tylicum, Streptococcus, and Staphylococcus aureus33,77–79 as
well as some Gram-negative species such as Campylobacter
jejuni and Neisseria gonnorhoeae.80,81 The PerR homodimer,
like Fur, carries one structural Zn2+ per monomer. It also
binds either Mn2+ or Fe2+ as ‘regulatory metals’ at a site that 25
is distinct to that occupied by the structural Zn2+,82,83 but it is
only the Fe-form of PerR that senses peroxides. Thus, sensi-
tivity to peroxides is dependent on the relative availabilities of
Mn and Fe since the Mn-co-factored form displays low
sensitivity to peroxide signals. Interestingly, B. subtilis pos- 30
sesses both a PerR and Fur that recognize very similar DNA-
binding sites yet still manage to control distinct sets of target
genes.84 In C. jejuni, there is some overlap between the Fur and
PerR regulons since the katA gene (encoding catalase) is
controlled by both regulators.85,86 This suggests that Fur 35
and PerR have evolved divergently from a common ancestor
by gene duplication, with one protein retaining its role in
controlling iron homeostasis while the second protein evolved
to specialize in responding to oxidative stress. A recent
transcriptome analysis revealed that the PerR regulon in C. 40
jejuni comprises 66 genes, including genes specifying oxidative-
stress defense enzymes (KatA, AhpC, a ferritin, the TrxB
thioredoxin and the NAD(P)H quinolone reductase, MdaB)
as well as its own gene.80 Similarly, the B. subtilis PerR regulon
comprises a large number of genes (75), that likewise includes 45
katA, ahpC, as well as perR itself.87 Fig. 4 summarizes the
involvement of the E. coli Fur protein in the response to
oxidative stress.
50
Regulators of oxidative stress response
Redox-active groups, such as cysteine-thiols or iron (as heme,
[Fe–S] or mononuclear iron), are often present in redox-stress
responsive transcriptional regulators where they act as sensors 55
mediating a conformational change that adjusts interaction
with target DNA sequences and thus influences the transcrip-
tion of cognate genes.88 Cysteine residues have the capacity to
sense redox signals through oxidation, which can promote the
Metallomics, 2011, ]]], 1–10 | 5
 1 1

5 5

10 10

15 15

20 20

25 25

Fig. 3 Regulation of iron uptake and storage by regulators belonging to the Fur family: Fur binds Fe2+, which allows it to contact a consensus
operator sequence overlapping with the promoter sequences. In H. pylori, apo-Fur acts as a repressor of the sodB gene (A). Fur-Fe2+ represses the
transcription of a small RNA (RyhB in E. coli) which normally destabilizes the mRNA for iron storage proteins, thereby acting indirectly as a
30 positive regulator (B). IdeR, DtxR-like iron regulator in mycobacteria, binds Fe2+ as co-repressor to repress the transcription of iron uptake genes 30
or it binds Fe2+ as co-inducer and contacts a DNA sequence upstream of the promoter, thereby acting as a direct activator of the transcription of
genes for iron storage proteins (C). The rhizobacterial Irr regulator binds heme after iron incorporation into the protoporphyrin IX (PPX); this
stimulates Irr degradation. When the level of iron is too low to ensure enough metallation of PPX, Irr is stable and free to both activate the
transcription of genes involved in the uptake of iron and down-regulate the genes for the biosynthesis of heme and for the storage of iron (D). Irr
also associates with ferrochelatase, although this is not shown in this figure.
35 35
formation of disulfide bridges which consequently alter pro- divergent) SoxS-encoding gene. SoxS is a simplistic MarR-like
tein conformation, thereby influencing regulatory activity.88 transcriptional activator that only consists of a single DNA-
binding domain (no effector domain is present, although it
MerR-like redox sensor: SoxR contains two HTH-DNA binding motifs) but is responsible for
40 40
direct transcriptional activation of the entire SoxRS regulon
SoxR senses and responds to redox-cycling agents (e.g. para-
(e.g. the Sod enzymes and O2-resistant dehydratases). This
quat) that stimulate the accumulation of superoxide inside the
unusual type of two-component regulation for superoxide/
cell through mediation of ‘elicit’ single-electron transfer pro-
redox-cycling agents is not observed in organisms other than
cesses.89 SoxR was originally thought to sense the superoxide
the enterobacteria. In some bacteria, SoxR homologues are
45 anion directly, but recent findings indicate that redox-cycling 45
present but do not control the ROS induction of Sod enzymes.
agents activate SoxR in the absence of oxygen and so this
For instance, for P. aeruginosa the SoxR-equivalent shows
finding excludes O2 as a direct SoxR effector.89 SoxR is a
77% sequence similarity with its E. coli counterpart but only
member of the MerR family of transcriptional activators
seems to control the induction of one efflux pump (MexGHI-
which include transcriptional activators responding to heavy
OpmD), which is thought to be involved in the export of the
50 metals (e.g. mercury). MerR-like proteins act by remaining 50
redox-active secondary metabolite pyocyanin.91,92 P. aerugi-
attached to the promoter in both the active and inactive state,
nosa SoxR is activated by the redox-cycling phenazine com-
but upon activation they catalyse distortion of the DNA
pound pyocyanin and does not seem to act as a paraquat-
duplex allowing the 35 and 10 boxes to reposition such
responsive regulator.92 Externally added pyocyanin was found
that they can engage RNA polymerase enabling open-complex
to cause a decreased expression of pyoverdine genes by an
55 formation. SoxR employs a [2Fe–2S] cluster to sense redox 55
unknown mechanism and it is thought that this activity assists
cycling agents. Such agents appear to reversibly oxidise the
in lowering the levels of free iron in the cell, thus relieving
SoxR [2Fe–2S] cluster, and thus activate SoxR-stimulated
redox stress.92
transcriptional activation.90 Interestingly, in E. coli, SoxR
directly controls just a single gene—the adjacent (and

6 | Metallomics, 2011, ]]], 1–10 This journal is 

c The Royal Society of Chemistry 2011
 1 1

5 5

10 10

15 15

20 20
2+ 2+
Fig. 4 Importance of Fur-Fe in the control of oxidative stress in the model bacterium E. coli: In wild-type E. coli (WT, top panel) Fur-Fe
represses the uptake of iron. This limits the amount of iron in the cell, thereby reducing the potential for production of ROS via the Fenton
reaction. Additionally, Fur-Fe2+ indirectly (via the RyhB regulatory RNA) activates the expression of genes encoding iron-storage proteins as well
as the Fe-cofactored superoxide dismutase SodB (and down-regulating the Mn-factored SodA). Transcription of fur is activated by the OxyR
25 regulator when it gets oxidized by H2O2 (and SoxRS in response to superoxide inducers; not shown). In mutants devoid of peroxidases (Hpx) the 25
levels of H2O2 rise considerably, damaging the Fur protein (probably by splitting it from its bound iron), which results in increased Fe uptake,
elevating the Fenton reaction, leading to the further destruction of [Fe–S] clusters. Likewise, Fur can no longer activate the transcription of sodB or
other iron-protein genes, leading to further increases in free iron as well as diminished Sod activity.

MarR-family redox sensors: PqrR and OhrR
30
P. aeruginosa contains a MarR-like regulator, PqrR, that
controls expression of a gene encoding a thioredoxin
(PqrABC) and contributes to resistance against paraquat as
well as to other oxidizing compounds.93 PqrR seems to sense
35 redox signals through an iron-containing prosthetic group
coordinated by conserved Cys residues. Unlike SoxR, PqrR
is a repressor and oxidation causes its release from the
operator sequence, allowing the transcription of the pqrABC
genes.93 OhrR is another member of the MarR family involved
40 in redox-stress regulation. Rather than an Fe-containing
sensor, this transcription factor utilises redox-sensitive cy-
steine residues (similarly to the H2O2-sensing OxyR protein).
It acts as a repressor when its sensory Cys residues are in the
reduced form, enabling de-repression upon oxidation (like
45 PqrR). OhrR responds to the presence of organic peroxides
and one of its major regulatory targets is a gene specifying a
thiol peroxidase. The OhrR regulator is found in B. subtilis,
Xanthomonas campestris and P. aeruginosa.94–99
50
The LysR regulator OxyR
OxyR is a redox sensor belonging to the LysR type transcrip-
tional regulator family (LTTR). It binds DNA as dimers or
tetramers using an N-terminal helix-turn-helix (HTH) DNA-
55 binding motif. Upon exposure to H2O2 (in excess of 100 nM)
or change in the cytoplasmic thiol-disulfide redox status, two
conserved cysteine residues in each monomer, Cys199 and
Cys208, form a reversible, intramolecular disulfide bridge
(S–S) that induces a conformational change triggering
tetramer formation and resultant transcriptional activation
30
of regulated genes.100–103 In E. coli, OxyR regulates several
peroxide-detoxifying enzymes, such as KatG (hydroperoxi-
dase I) and AhpCF (alkylhydroperoxide reductase). In addi-
tion, OxyR regulates several genes with other roles in oxidative
stress defense. Such genes include dps (a protective, non-
35
specific DNA binding mini iron-storage protein), fur (the iron
regulator), trxC (thioredoxin 2), gorA (glutathione reductase),
and grxA (glutaredoxin I); these have roles in maintaining
appropriate reduction status of cellular Cys residues or in the
management of free iron levels.104,105 It is somewhat revealing
40
to observe that OxyR collaborates with Fur in some cases: in
E. coli, OxyR induces fur transcription (which, appropriately,
would be expected to lower free iron levels during redox stress)
and jointly (along with Fur) controls fhuF which encodes a
ferric reductase, a [2Fe–2S]-protein required for release of iron
45
from certain siderophores.105 It should be noted that SoxRS
also activates fur transcription in E. coli104), so iron uptake is
likely to be down-regulated by both redox-cycling agents as
well as H2O2. For P. aeruginosa, OxyR appears indispensible
for growth under conditions of extreme iron limitation, despite
50
continued production of the siderophore pyoverdine and
unabated uptake of ferripyoverdine.106 One possible explana-
tion is that the release of iron from ferripyoverdine by a
periplasmic reductase is sensitive to ROS. A similar growth
defect is observed when P. aeruginosa oxyR mutants are
55
propagated at high (>20 mM) FeCl3 concentrations.106 These
results suggest that the extremely redox-stress sensitive P.
aeruginosa oxyR mutant is unable to cope with either iron
limitation or excess. As in E. coli, Fur levels are decreased by

This journal is 
c The Royal Society of Chemistry 2011 Metallomics, 2011, ]]], 1–10 | 7
 1 accumulation of toxic levels of iron which can promote ROS 1
production, whilst mounting a strong anti-oxidative stress
response is apparently necessary in the management of iron
homeostasis. There can be little doubt that future studies will
5 reveal further elaborate inter-connections between the iron 5
and oxidative stress regulons as suggested by the recent
discovery of a role for manganese as ‘anti-oxidant metal’ that
appears to partly replace iron under oxidative-stress
conditions.
10 10
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