Subsystem: Campylobacter Iron Metabolism

This subsystem's description is:

Iron is an essential nutrient for all living organisms, as it is a cofactor of many enzymes, and plays an important role in electron transport and redox reactions. Conversely, uncontrolled iron uptake causes iron toxicity and oxidative stress, leading to cessation of growth. Therefore maintenance of iron homeostasis is of critical importance to living organisms. In bacteria, this is usually achieved by balancing the uptake and storage of iron.
Campylobacters have developed iron binding and transport systems which allow them to acquire sufficient iron for growth (See review: van Vliet AH, Ketley JM, Park SF, Penn CW. The role of iron in Campylobacter gene regulation, metabolism and oxidative stress defense. FEMS Microbiol Rev. 2002 Jun;26(2):173-86).

===========SUBSETS OF ROLES:=========================

Iron_transport – 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23
Iron_storage –24,25,26,27
Iron-responsive_regulatory_systems – 28,29
Ferrous_iron_uptake – 1,2,3
Enterochelin_uptake – 4,5,6,7
Heme_uptake – 8,9,10,11
Ferric_iron_transporter_system - 15,16,17,18

For more information, please check out the description and the additional notes tabs, below

Literature ReferencesHeme utilization in Campylobacter jejuni. Ridley KA Journal of bacteriology 2006 Nov16980451
The role of iron in Campylobacter gene regulation, metabolism and oxidative stress defense. van Vliet AH FEMS microbiology reviews 2002 Jun12069882
Cloning and characterization of a Campylobacter jejuni iron-uptake operon. Galindo MA Current microbiology 2001 Feb11136137
DiagramFunctional RolesSubsystem SpreadsheetDescriptionAdditional Notes 

Oops! We thought there was a diagram here, but we can't find it. Sorry

Group Alias
Abbrev.Functional RoleReactionsScenario ReactionsGOLiterature
SubsetsColoring
collapsed
expanded


  
Taxonomy Pattern 
Organism 
Domain
Variant [?] 
active
CeuECeuDCeuBCeuCCfbpACfbpBCfrAExbBExbDTonBFurFeoAFeoBChuCChuAChuDChuBHIBCorAFTp19PerRBFTChuZHAPCfbpCCfbpLpCjrAPSR
Iron is an essential nutrient for all living organisms, as it is a cofactor of many enzymes, and plays an important role in electron transport and redox reactions. Conversely, uncontrolled iron uptake causes iron toxicity and oxidative stress, leading to cessation of growth. Therefore maintenance of iron homeostasis is of critical importance to living organisms. In bacteria, this is usually achieved by balancing the uptake and storage of iron.
Campylobacters have developed iron binding and transport systems which allow them to acquire sufficient iron for growth (See review: van Vliet AH, Ketley JM, Park SF, Penn CW. The role of iron in Campylobacter gene regulation, metabolism and oxidative stress defense. FEMS Microbiol Rev. 2002 Jun;26(2):173-86).

===========SUBSETS OF ROLES:=========================

Iron_transport – 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23
Iron_storage –24,25,26,27
Iron-responsive_regulatory_systems – 28,29
Ferrous_iron_uptake – 1,2,3
Enterochelin_uptake – 4,5,6,7
Heme_uptake – 8,9,10,11
Ferric_iron_transporter_system - 15,16,17,18
--------------A. Iron transport --------------------------

The soluble ferrous iron (Fe2+) is readily available for bacteria, and requires only transport over the inner membrane of Gram-negative bacteria. In the presence of oxygen at pH≥7, ferrous iron is rapidly converted into ferric iron (Fe3+), which is almost completely insoluble at pH≥7.
In response to iron restriction, many bacterial and fungal species produce small iron-chelating molecules called siderophores, which make chelated or precipitated ferric iron available for acquisition. However, complexed ferric iron poses a problem for Gram-negative bacteria, as ferric iron complexes are too large to be transported through the porins of the outer membrane (OM). Bacteria have solved this by either transporting ferric iron complexes via high-affinity OM receptors, or removing iron from the complex followed by transport over the OM. Transport over the cytoplasmic membrane (CM) is subsequently mediated by ABC transporters.

*1. Ferrous (Fe2+) iron uptake - FeoB and CorA

Transport of ferrous iron requires only a cytoplasmic membrane transporter. The first bacterial ferrous iron-specific transport system identified was the Feo transport system of Escherichia coli. This system consists of the feoAB operon, which encodes a small protein (FeoA) of unknown function, and the FeoB transporter protein.
The C. jejuni genome contains a gene encoding a FeoB homolog (Cj1398), which is located downstream of and probably in an operon with a small gene (Cj1397) encoding a protein of 74 amino acids, which displays only 16% overall identity to the E. coli FeoA protein.

In environments with restricted magnesium availability (e.g. inside eukaryotic cells) CorA has been reported to transport iron. This might be of relevance to C. jejuni, which is invasive. The C. jejuni genome encodes a homolog of CorA (Cj0726c), but this transporter homolog has not been studied so far.

*2. Siderophore uptake - Enterochelin and Ferrichrome

Enterochelin uptake:
Campylobacter species are not thought to produce siderophores, yet they are able to utilize both ferrichrome and enterochelin as sources of iron.
The Ceu (Cj1352–Cj1355) system encodes the components of a binding protein-dependent CM ABC transport system, most likely specific for the siderophore enterochelin ( Ref.2). Phenotypic and genetic analyses of this system showed it to comprise two hydrophobic integral membrane proteins, CeuB (35.5 kDa) and CeuC (34.8 kDa), which may form the cytoplasmic membrane permease, an ATP-binding protein, CeuD (28.8 kDa), and a periplasmic substrate-binding protein, CeuE (34.5 kDa).

Ferrichrome uptake

There seems to be variability between C. jejuni strains with regard to the presence of some of the iron acquisition systems. The cfhuABD operon is not present in the genome of C. jejuni NCTC11168, and was only present in six out of 11 tested strains.

*3. Heme uptake

ChuA - a 70-kDa OM protein, was identified as a Fur- and iron-repressed protein, and showed a significant similarity to OM siderophore receptors of other bacteria. On the C. jejuni NCTC11168 genome, the chuA (Cj1614) gene is followed by the chuB, chuC and chuD (Cj1615–Cj1617) genes, which encode the predicted components of an ABC transporter system. ChuB is a CM permease, ChuC an ATPase and ChuD a periplasmic binding protein ( Ref.3 ).

*4. Other iron uptake systems

CfrA

The iron- and Fur-repressed cfrA (Cj0755) gene was originally identified in C. coli by sequence analysis of the region downstream of one of the two 23S rRNA gene copies. The CfrA protein is similar to a long list of bacterial TonB-dependent OM siderophore receptors. Like the cfhuABD operon, the cfrA gene was not present in all tested strains, and it is tempting to speculate that C. jejuni strains will either contain the cfrA gene or the cfhuABD genes.

Cj0177–Cj0178:

Analysis of OM profiles of a C. jejuni NCTC11168 fur mutant indicated that there was a third Fur- and iron-regulated OM protein (Iro80), but this protein was not further characterized. The Iro80 protein is probably encoded by the Cj0178 gene, and the protein displays significant homology to the PhuR hemin receptor and the CjrB colicin receptor, but its function in C. jejuni is currently unknown.

Cj0173c–Cj0176c:

The Cj0173c–Cj0176c genes encode a putative ferric iron transporter system homologous to periplasmic binding protein-dependent iron transport systems of several Gram-negative bacteria. This system was designated the Campylobacter ferric binding protein (Cfbp) system. Based on sequence similarity, CfbpC (Cj0173c) is most likely the ATPase protein, CfbpB the permease protein, and CfbpA the periplasmic binding protein. The cfbp operon is preceded by a small gene encoding a putative lipoprotein of 43 amino acids (including its signal sequence). This protein is not present in other bacterial Cfbp-like systems, and is not homologous to any protein present in the sequence databases.

Cj1658–p19

On the C. jejuni genome, the p19 (Cj1659) gene is preceded by the Cj1658 gene that encodes a putative membrane protein of 75 kDa. Homologs of the Cj1658 and p19 proteins are found on the 102-kb iron uptake pathogenicity island of Y. pestis, and together with the observed iron and Fur regulation of p19, this suggests a role of these proteins in iron uptake of C. jejuni.

*5. Accessory factors

Transport of substrates over membranes consumes energy, and for the OM receptors, this energy is derived from the proton motive force over the CM. The energy is transduced by the TonB protein, which forms a complex with the ExbB and ExbD proteins, and bridges the periplasm to contact the OM receptor.
In C. coli and C. jejuni, a tonB gene (Cj0753c) is located divergently to the cfrA gene. The C. jejuni NCTC11168 genome encodes two other TonB homologs (Cj1630 and Cj0181). It is unknown whether these two genes also exist in C. coli, thus it is possible that the phenotype of the tonB (Cj0753) mutation is C. coli-specific. There are also three exbB and exbD genes, of which two sets (Cj0179–0180 and Cj1628–1629) are transcriptionally coupled to a tonB gene.
-----------------------------------------------------------------------------------------------
B. Iron storage

Iron that is not used directly needs to be stored in a non-reactive state, in order to prevent formation of hydroxyl radicals, thus protecting the cell from iron toxicity.

Ferritin and Bacterioferritin - There are two classes of bacterial iron storage proteins, the ferritins and bacterioferritins. The C. jejuni genome encodes both a ferritin, the Cft (Cj0612c) protein, and one putative bacterioferritin, the Cj1534c protein ( Ref. 5).

Iron binding proteins - There is a family of C. jejuni genes that encode proteins displaying homology to the eukaryotic iron and oxygen binding hemerythrin proteins, and have most or all the iron binding residues conserved. Another iron binding protein, Cj0012c, displays homology to rubrerythrins, a class of proteins which contain a unique combination of a rubredoxin-like [Fe(SCys)4] domain and a non-sulfur oxo-bridged di-iron center.
------------------------------------------------------------------------------------------

C. Campylobacter iron-responsive regulatory systems

Campylobacter has developed two similar and possibly overlapping regulatory mechanisms which both use iron as the environmental signal:
1. Fur - Ferric uptake regulation protein
2. PerR - Peroxide stress regulator

Fur homologs are members of class of metal-responsive regulatory proteins, which are ubiquitous in both Gram-negative and Gram-positive bacteria. These histidine-rich polypeptides regulate important processes like metal homeostasis, oxidative stress defense and acid resistance. In general, Fur homologs have two domains: the C-terminal part is responsible for metal binding and dimerization and the N-terminal part mediates DNA recognition and binding.
Since PerR regulation is also a requirement for full virulence of S. aureus , it is very much possible that PerR plays a similar role in virulence of Campylobacter.

======= REFERENCES:========================================

1. van Vliet AH, Ketley JM, Park SF, Penn CW. The role of iron in Campylobacter gene regulation, metabolism and oxidative stress defense. FEMS Microbiol Rev. 2002 Jun;26(2):173-86. Review.PMID: 12069882

2. P.T. Richardson and S.F. Park , Enterochelin acquisition in Campylobacter coli: characterization of components of a binding-protein-dependent transport system. Microbiology 141 (1995), pp. 3181–3191.

3. J.D. Rock, A.H.M. van Vliet and J.M. Ketley , Haemin uptake in Campylobacter jejuni. Int. J. Med. Microbiol. 291 Suppl. 31 (2001), p. 125.

4. M.A. Galindo, W.A. Day, B.H. Raphael and L.A. Joens , Cloning and characterization of a Campylobacter jejuni iron-uptake operon. Curr. Microbiol. 42 (2001), pp. 139–143.

5. S.N. Wai, K. Nakayama, K. Umene, T. Moriya and K. Amako , Construction of a ferritin-deficient mutant of Campylobacter jejuni: contribution of ferritin to iron storage and protection against oxidative stress. Mol. Microbiol. 20 (1996), pp. 1127–1134.

6. Ridley KA, Rock JD, Li Y, Ketley JM. Heme utilization in Campylobacter jejuni. J Bacteriol. 2006 Nov;188(22):7862-75. Epub 2006 Sep 15. PMID: 16980451
============================================================================================