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Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

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Helicobacter pylori: Physiology and Genetics.

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Chapter 17Ion Metabolism and Transport

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1 Department of Medical Microbiology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Academic Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
2 Department of Microbiology, Institute of Medical Microbiology and Hygiene, University of Freiburg, Hermann-Herder-Str. 11, D-79104, Freiburg, Germany

Ions play an important role in the metabolism of all organisms as reflected by the wide variety of chemical reactions in which they take part. Ions are cofactors of enzymes, catalyzing basic functions such as electron transport, redox reactions, and energy metabolism; and they also are essential for maintaining the osmotic pressure of cells. Because both ion limitation and ion overload delay growth and can cause cell death, ion homeostasis is of critical importance to all living organisms. In bacteria, this is achieved by balancing their uptake, efflux, utilization, and storage (Fig. 1).

Figure 1

Figure 1

. Schematic representation of the mechanisms involved in maintaining ion homeostasis.

Helicobacter pylori colonizes the gastric mucosa of humans, and this niche provides a challenging milieu with continuous changes in environmental conditions, including the concentration of ions. Despite a comparatively small genome of approximately 1,700 kb, H. pylori must be well adapted to this environment, as colonization is usually lifelong. The first successful cultivation of H. pylori was reported only in 1983 (69, 117), and since then a wealth of research on this important pathogen has followed. Most of the initial investigations focused on diagnostics, treatment, epidemiology, and virulence factors of H. pylori, and not on other fundamental issues such as physiology and metabolism. However, the publication of the complete genome sequence of two H. pylori strains has promoted more detailed studies of the physiology and metabolism of this interesting pathogen. Gastric helicobacters are unique among microorganisms in their colonization of the gastric mucosa. For this reason H. pylori serves as a model organism that is well suited for the study of bacterial adaptation mechanisms and host-pathogen interactions.

This review concentrates on the mechanisms used by H. pylori to maintain its ion homeostasis, emphasizing metal cations. To date, most H. pylori studies have focused on nickel and iron cations and resistance to heavy metals and to acid. There is little information available on other cations or anions, and assignment of putative functions to different ions is only by homology to the (metallo)enzymes of other organisms. Since resistance to acid is discussed in a separate chapter, H+ homeostasis is not treated here. H. pylori genes will be described by the HP numbering of the genome sequence of H. pylori 26695 (108).

Ion Homeostasis

Ions participate in a great variety of cellular processes and are essential for cell growth. Imbalance of the cytoplasmic concentration of ions leads to a multitude of stresses, for example, those caused by changes in osmolarity, acid, metal toxicity, or oxidative damage. Maintaining ion homeostasis requires both sensor systems to detect the cytoplasmic ion concentration and effector systems to restore normal cell conditions, or to cope with stress caused by ion imbalance. For most ions, the cell can affect homeostasis through regulation of the expression or the activity of its uptake and efflux systems. Since import of many cations appears to be relatively nonspecific, the corresponding regulatory mechanisms are probably based mainly on ion-specific efflux pumps. For some ions the existence of cytoplasmic storage proteins allows for more complex homeostasis mechanisms. Ion storage proteins remove excess ions from the cytoplasm and keep them in a nonreactive form, which can be accessed when the ion becomes scarce.

The ion-responsive regulatory systems of bacteria usually consist of a single regulatory protein that combines sensor and effector functions in one molecule. It senses the cytoplasmic ion concentration and, when activated, can induce or repress transcription of the corresponding uptake, efflux, and/or storage systems. H. pylori contains relatively few regulatory proteins (15), but these include homologs of the iron-responsive regulator Fur and the nickel-responsive regulator NikR (27, 30, 113). Storage systems have been identified only for iron and possibly nickel, and they are described below. Since overload of both iron and nickel results in the generation of oxidative damage, a brief description of mechanisms dealing with oxidative stress in H. pylori is included.

Iron Homeostasis

Regulation of iron uptake

Iron availability is usually low in most environments, and thus bacteria require specific high-affinity iron acquisition systems, which are discussed in the "Ion Transport" section. Bacteria regulate their iron-uptake and iron-storage systems in response to the cytoplasmic Fe2+ concentration (21). When this concentration becomes too high, bacteria switch off their high-affinity iron uptake systems. These iron-responsive systems are mediated by the ferric uptake regulator (Fur) protein, which acts mostly as an iron-activated transcriptional repressor (38). In some cases Fur can also mediate induction of transcription in response to iron (34). Fur homologs, which are widely distributed in eubacteria, are thought to bind their operator DNA sequences only when sufficient Fe2+ is available in the cytoplasm, thus modulating the transcription of the regulated genes. In the absence of Fur-Fe2+ complexes, the regulator stays and transcription of Fur-regulated genes is not affected. Availability of free iron is normally restricted in the animal host, and pathogenic microorganisms often use low-iron conditions as a stimulus for the concerted activation of virulence factors, which can be mediated through Fur homologs (66).

H. pylori contains a Fur homolog (HP1027) shown to function as a metal-responsive regulator (911, 114). The mutational inactivation of fur in H. pylori, as well as an H. pylori-adapted Fur titration assay (FURTA-Hp) (40), allowed the identification of several genes that are either directly or indirectly regulated by Fur (9, 17, 40, 114). In contrast with other bacteria, Fur regulates some but not all putative iron-uptake systems of H. pylori. This suggests that under high iron conditions H. pylori is able to restrict but not close down completely its uptake of iron. However, when iron is scarce, H. pylori can express additional iron-acquisition systems securing sufficient iron (114).

Iron storage

Continuous uptake of iron creates the need for removal of iron from the cytoplasm and storage of excess iron. This protects the cell from iron toxicity and also provides for an iron deposit, which is available when iron is scarce. Bacterial iron storage proteins can be divided into two classes: ferritins and bacterioferritins. Their most important structural difference is that bacterioferritins usually contain heme, whereas ferritins do not (2). Bacterioferritins are composed of 24 subunits and are able to store approximately 4,500 iron atoms per molecule (2, 19). Recently a new subgroup of bacterioferritins has been described that form an oligomer of 12, rather than 24 subunits, and only store approximately 500 iron atoms per molecule (19). H. pylori contains one ferritin, the 19-kDa prokaryotic ferritin (Pfr) protein (HP0653), and one putative bacterioferritin, the HP-NAP protein (HP0243).

This Pfr is similar to eukaryotic H-chain ferritins and to other prokaryotic ferritins (33, 41). It serves as an intracellular iron deposit and protects H. pylori against iron toxicity (14), and iron stored in Pfr can be released and reused to support growth under iron-limited conditions (116). The protective function of Pfr against metal overload may not be limited to iron, as shown by the increased sensitivity of a Pfr-negative mutant to manganese, copper, and cobalt (10, 14). These mutants showed a significant decrease in the iron uptake capacity (10) and increased resistance to oxidative stress (116).

The H. pylori neutrophil activating protein (HP-NAP) was originally isolated as an immunodominant protein that activates neutrophilic granulocytes in vitro (39). It was subsequently shown also to mediate adhesion of H. pylori to mucin (82). The HP-NAP protein is homologous to both bacterioferritins and the DNA-binding proteins of the Dps family (109). HP-NAP binds iron, and the three-dimensional structure of HP-NAP provides strong evidence that the protein represents a member of the recently discovered 12-subunit ferritin family (19). A role of HP-NAP in H. pylori iron storage has been suggested, but it is yet to be demonstrated (109).

Regulation of iron storage

Iron homeostasis requires regulation of iron storage systems (Fig. 1). Expression of Pfr is induced by iron and repressed under iron-restricted conditions (14). This enables the bacteria to increase storage of iron if excess environmental iron is available and to secure availability of free cytoplasmic iron when it is scarce. Pfr expression is repressed under iron-restricted conditions in wild-type strains but is constitutive in the fur mutant, suggesting that Fur represses pfr transcription under iron-restricted conditions. This is unusual because in other bacteria the Fur protein is thought to be inactive in the absence of iron. However, the regulation of bacterial iron storage has not been investigated in detail, and the function of Fur still is not completely understood. H. pylori Fur also seems involved directly in downregulation of ferritin synthesis in response to other metals (9), and plays a role in nickel-responsive induction of urease expression in H. pylori (113). Although a Fur-negative mutant showed no obvious growth deficiencies, it was more sensitive to increased levels of transition metals (10). This suggests that H. pylori Fur represents a more global metal-dependent regulator that orchestrates the expression of metalloenzymes in response to the availability of different metal ions. Interestingly, the H. pylori fur mutants display reduced acid resistance, underlining the central role of this regulator in the control of ion homeostasis (17).

Nickel Homeostasis

Nickel regulation

Recently, a nickel-responsive gene regulator, designated NikR, was identified in Escherichia coli (30). Similar to iron regulation by Fur, when free nickel is available NikR binds to the promoter of the E. coli nikA gene, which encodes a periplasmic nickel-binding protein and represses transcription of the nikAB-CDE nickel acquisition system (23, 24, 30). H. pylori contains a NikR homolog (HP1338), which displays amino acid identity of 30% and similarity of 55% to the E. coli protein. Surprisingly, preliminary studies have shown that mutational inactivation of the H. pylori nikR gene does not affect expression of urease or the GroELS chaperone proteins, which are involved in nickel metabolism of H. pylori (27, 63, 113). Possible targets of H. pylori NikR are the nickel acquisition system encoded by the genes nixA and abcCD (see "Nickel Transport," below). Further studies will be required to establish the precise function of NikR in H. pylori.

Nickel storage

The H. pylori Hpn (HP1427) protein was initially isolated through its binding to nickel and zinc in vitro (49). Hpn is a small (7-kDa) protein that has a very high histidine and cysteine content (28 His and 4 Cys in 60 amino acids total) (49). Hpn is thought to play an important role in protection against nickel toxicity, possibly by binding excess cytoplasmic nickel. In line with a putative nickel storage or scavenging function, H. pylori Hpn-negative mutants are significantly more sensitive to nickel overload but not to cobalt and copper (77). These mutants were also not affected in their urease activity, indicating that Hpn is not required for nickel transport or urease apo-protein activation (49). Although Hpn also forms complexes with zinc in vitro, resistance to zinc was not affected in the H. pylori hpn mutant (77).

Defense against Oxidative Stress

H. pylori requires oxygen for optimal growth. However, in combination with oxygen, divalent metals contribute to the generation of reactive oxygen species such as superoxides and hydroxyl radicals through the Haber-Weiss and Fenton reactions (74, 110). Superoxide and hydroxyl radicals damage lipids, proteins, and DNA by oxidation, and cells will attempt to remove superoxide and peroxides before they cause significant damage. In H. pylori, this is mediated by the enzymes superoxide dismutase (SodB) (HP0379), catalase (HP0875), and probably alkyl hydroperoxide reductase (HP1563) (87, 88, 90, 103). SodB activity seems to be essential for H. pylori, as the sodB gene could not be inactivated (12). The heme-cofactored catalase, however, is not essential in vitro, as H. pylori catalase-negative naturally occurring mutants (68, 119) and mutants constructed by insertional mutagenesis (87) have been readily isolated. In contrast to other bacteria, both SodB and catalase are present on the H. pylori cell surface (80) and are thought to protect H. pylori from toxic oxygen metabolites produced by activated immune cells in the inflamed gastric mucosa. It has also been suggested that secretion of SodB and catalase might also function as decoy for the evasion of the immune response (80). A more detailed discussion of the functions of these enzymes is given in chapter 15.

Ion Metabolism

The adaptation of H. pylori to life in the gastric mucosa seems to have led to a more pronounced role of nickel in its metabolism, for example, in its role as an essential cofactor of urease, which mediates acid resistance of H. pylori. In contrast, relatively little is known about the role of other ions in H. pylori metabolism. This section gives a brief overview of H. pylori metabolic processes in which metal cations act as cofactors; this information was obtained from genome analyses and sparse experimental data.


H. pylori expresses large amounts of urease, and levels can reach up to 10% of total cellular protein (3). Urease contains 12 nickel atoms per molecule, and thus H. pylori has a relatively high demand for nickel. Native H. pylori urease is a multimeric protein that consists of six UreA and six UreB subunits (35). The active site of each UreB subunit contains two nickel ions (54, 78), and without these ions the urease apoenzyme is not active (57). Nickel is inserted into the urease apoenzyme by the UreE, UreF, UreG, and UreH proteins (29). Urease plays a central role in the pathogenesis of H. pylori infection (75) and catalyzes the conversion of urea into carbon dioxide and ammonia. The latter is able to neutralize gastric acid and offer protection to H. pylori against the low pH in the stomach (64, 99, 118). In addition, ammonia may be used as a nitrogen source supporting growth of H. pylori (45). Another important H. pylori enzyme, likely to contain nickel, is a hydrogen uptake NiFe hydrogenase (67). Like NiFe hydrogenases from other bacteria, it is involved in electron transfer and respiration and subject to anaerobic activation (67). A detailed discussion of urease structure and function is given in the chapter devoted to this enzyme.


Iron is an essential nutrient for all living organisms, with the exception of some lactobacilli. Iron is a cation that exists in the ferrous (Fe2+) and ferric (Fe3+) states. The redox potential of Fe2+/Fe3+ in biomolecules spans a range from +300 to −500 mV, which makes iron well suited for participating in electron transfer reactions. In addition, iron interacts chemically with oxygen, sulfur, and nitrogen ligands, allowing coordination of the iron atom in the active sites of enzymes with different redox potentials depending on the protein environment surrounding the complexed iron (21, 36). Iron-containing proteins are mostly involved in basic cell metabolism. Ferroprotoporphyrin (heme) groups are essential moieties of many enzymes involved in bacterial respiration, electron transport, and peroxide reduction. Iron-sulfur proteins participate in electron transport reactions, anaerobic respiration, amino acid metabolism, and energy metabolism. Finally, iron-containing non-heme, non-iron-sulfur proteins are required for DNA synthesis, protection from superoxide, and amino acid biosynthesis (36).

Potassium and Sodium

Potassium is the predominant cation in the bacterial cytoplasm and also is the main ion involved in the adaptation to changes in osmolarity. The first response of bacteria when adapting to environmental high osmolarity is to increase the uptake of potassium (28). Adaptation to a low osmolarity medium leads to the efflux of potassium and other osmotic solutes through nonspecific channel proteins (28). The response of H. pylori to either type of osmotic shock has not been extensively characterized, but there are indications that H. pylori regulates some of its heat shock chaperone proteins in response to salt and/or osmotic stress through the HspR regulatory protein (104).

The function of sodium in bacterial metabolism is predominantly in symporter and antiporter systems for different nutrients. It also functions in maintaining the proton gradient necessary for the proton motive force, and thus has a role in energy production (52).


Magnesium is the most abundant divalent cation in living cells and often functions in conjunction with ATP in many enzymatic reactions. This cation is often found bound to cellular polyanions such as nucleic acids and lipids, and owing to its being mostly complexed, magnesium does not contribute much to osmotic processes (100, 102). In H. pylori the use of magnesium as cofactor has been demonstrated for its phospholipase/sphingomyelinase (N-SMase) enzyme (22). N-SMase is produced in vivo since it elicits an immune response in H. pylori-positive patients and is thought to contribute to the pathogenesis of H. pylori infection through its actions against epithelial cell membranes (22). Magnesium is a cofactor of many enzymes catalyzing modification, replication, and transcription of nucleic acids, and as such, the restriction-modification systems of H. pylori are likely candidates to be magnesium-requiring enzymes (15). In other bacterial pathogens such as Salmonella enterica serovar Typhimurium and Bordetella pertussis, magnesium is an important signal for the concerted expression of virulence genes (44, 97). Indirect support for a similar function in H. pylori was derived from the effects of an aluminium-hydroxide-magnesium-hydroxide (co-magaldrox) combination drug that inhibits bacterial adhesion and interleukin 8 (IL-8) secretion and decreases expression of HSP60 on the surface of the bacterium.


Zinc metalloenzymes are for the most part involved in catalytic reactions. Alcohol dehydrogenases, which use zinc as a cofactor, convert alcohol to acetaldehyde. H. pylori contains one or two zinc-alcohol dehydrogenases, which may contribute to the damage to the gastric epithelium (61, 96). The bacterium also displays zinc-dependent protease activity (120), and a membrane-bound protein (HP1069) homolog of E. coli FtsH has been identified. FtsH has a strong similarity to a family of eukaryotic ATPases and has been suggested as a component of a proteolytic system in E. coli. FtsH homologs are involved in the proteolytic degradation of unstable proteins that can include both soluble regulatory proteins and membrane proteins (6, 48, 73, 98). In H. pylori, however, homologs of the other proteins of such a proteolytic system have not been found yet. Finally, zinc is a cofactor of the tRNA-modifying enzyme tRNA-guanine transglycosylase Tgt (HP0281), which assists in maintaining fidelity of translation (8, 93, 94).

Trace Metals

Bacteria also require trace amounts of metals such as copper, molybdenum, cobalt, and manganese, which commonly are toxic when present at high concentrations. The roles of most of these trace metals in H. pylori metabolism are as yet unknown. Some enzymes containing trace metals have been identified in H. pylori and are briefly reviewed here.


Owing to its two oxidation states, copper is well suited for participation in electron transfer reactions. It is present in the cb-type cytochrome oxidase of H. pylori that functions as a terminal oxidase in the respiratory chain. This important enzyme also contains three iron-containing heme groups (81, 112).


This ion is taken up as molybdate (MoO42−) and converted into molybdopterin, which is the cofactor of several enzymes involved in the reduction of alternative electron acceptors (36, 50, 92). Although the H. pylori genome does not contain orthologs of molybdoenzymes, there are at least 11 genes encoding orthologs of proteins involved in molybdopterin biosynthesis (1, 108). This suggests strongly that molybdenum is also essential for H. pylori, but its role in the metabolism of the bacterium requires further investigation.

Ion Transport

The cytoplasm of gram-negative bacteria is surrounded by two membranes, an inner cytoplasmic membrane (CM) and an outer membrane (OM). Ions transported to the cytoplasm have to cross both membranes. The OM contains porins with a general exclusion limit of approximately 600 Da that allow diffusion and transport of ions into and out of the periplasm (85). Ions that have reached the periplasm via porins cannot penetrate the CM, and specific transport systems have evolved for ion transport through the CM.

Two types of ion CM transporters are commonly found in bacteria. The first class consists of multicomponent ABC-transporters, which have one or two membrane-spanning permeases, one or two ATPase proteins, and in many cases a binding protein that concentrates the substrate in the periplasm and delivers it to the permease-ATPase complex. Transport by ABC transporters uses ATP as the energy source. The second type of CM transporter is the one-component transporter, which uses either ATP or the proton motive force to supply energy for the transport. An overview of ion transport systems identified in H. pylori is given in Fig. 2.

Figure 2

Figure 2

. Schematic overview of ion transport systems of H. pylori. The ion transported and the direction of transport are indicated. OM, outer membrane; CM, cytoplasmic membrane. Ion transporters are grouped depending on the direction of transport: importers (more...)

Nickel Transport

H. pylori has a high demand for nickel as cofactor for its urease enzyme and thus requires high-affinity transport systems to scavenge nickel from environments usually low in nickel. The concentration of this ion in human serum is very low (2 to 11 nM), and the nickel concentration in ingested food varies significantly depending on the diet and on food sources (25, 106). Nickel might be transported by the magnesium transporter CorA when the magnesium concentration is low, but this is thought to be of little relevance under physiological conditions (102). Specific nickel transporters have been described in other bacteria: the one-component transporters like the Ralstonia eutropha HoxN protein, and the multicomponent ABC transporters like the E. coli NikABCDE system (37).

The first nickel transporter identified in H. pylori was the NixA protein (HP1077), a member of the HoxN-like one-component class of nickel transporters (76). NixA is a 37-kDa protein located in the CM and contains eight transmembrane domains (42, 43). Transport through NixA does not seem to be specific for nickel, and it has been suggested that it can transport also cadmium, cobalt, and zinc (42). Nonetheless, the high affinity of NixA for nickel makes it very suitable to supply the high nickel demand of H. pylori (76). A nixA mutant constructed by insertional inactivation displayed significantly decreased nickel transport and urease activity (4), although they were not completely abolished in this mutant, indicating that H. pylori has additional nickel transport systems. Homology searches of the H. pylori genome sequence allowed the identification of the abcC gene (HP1576) (55), which encodes a protein ortholog of the NikD ATPase of E. coli Nik, a nickel ABC transporter system (83). The adjacent abcD gene (HP1577) encodes a protein with low homology to CM permeases. An H. pylori abcD mutant was severely affected in its urease activity, but an abcC mutant showed the same phenotype as the nixA mutant. An abcC nixA double mutant has only residual urease activity, indicating that nickel uptake was almost completely abolished (55). The H. pylori AbcCD system lacks a homolog of the E. coli NikA periplasmic binding protein, which binds nickel ions and carries them to the CM transporter. This suggests that the AbcCD system functions differently from the Nik system or that the homology between the putative H. pylori nickel-periplasmic binding protein and E. coli NikA is too low to identify an H. pylori NikA homolog.

The nixA and abcCD mutational studies demonstrate that H. pylori has two separate nickel acquisition systems, and this manifests the importance of nickel in H. pylori metabolism. A detailed discussion of NixA and nickel transport is also found in chapter 16.

Iron Transport

Soluble ferrous iron ions would be readily available for uptake by bacteria, but these ions are stable only under anaerobic and acidic conditions, because the presence of oxygen causes a rapid conversion to the ferric state, which is almost completely insoluble at a pH of ≥7. In tissues of human or animal hosts, the concentration of free iron is too low to support bacterial growth, as most iron is complexed into hemoglobin or chelated by transferrin in serum or by lactoferrin (Lf) at mucosal surfaces. Complexed iron poses a problem for bacteria, since these complexes are too large to be transported through the porins of the OM. Thus, uptake of iron complexes requires either high-affinity transport mediated by OM receptors or removal of the iron from the complex followed by transport (20, 21).

Unlike many other organisms, H. pylori does not synthesize the small iron-chelating molecules called siderophores, which make chelated or precipitated ferric iron available for acquisition by cells (36, 84). This is confirmed by analysis of the H. pylori genome sequence, which does not contain homologs of siderophore synthesis genes (15). Compared to the range of iron compounds that other bacterial pathogens like E. coli and S. enterica serovar Typhimurium can utilize, the number used by H. pylori is limited. Feeding assays indicate that H. pylori uses only very few siderophores produced by other organisms (13, 32, 58, 59). This limitation regarding iron acquisition may have developed owing to the absence of competition for nutrients by other microorganisms and the relatively low number of iron compounds available in the human stomach. Iron sources available in the gastric mucosa are Lf-bound iron, heme compounds released from damaged tissues, and iron derived from pepsin-degraded food. As the conditions in the gastric lumen and mucosa are predicted to stabilize the soluble ferrous iron, it is likely that, in contrast with many other bacterial pathogens, ferrous iron uptake plays an important role for H. pylori.

Ferrous iron uptake

Ferrous iron ions pass freely through the OM porins but require transport over the CM. In E. coli and S. enterica serovar Typhimurium, these ions are transported by the Feo system, comprising the FeoA and FeoB proteins (62, 111). The FeoB protein is located in the CM and hydrolyzes ATP to generate energy for the transport process. The function of FeoA is not known, although in E. coli it is essential for ferrous iron transport (62). The H. pylori genome encodes a homolog of FeoB (HP0687), but there is no obvious FeoA homolog. FeoB is required for high-affinity ferrous iron ion uptake into H. pylori (115). Isogenic feoB mutants not expressing the protein were unable to colonize the gastric mucosa of mice, indicating the importance of FeoB-mediated iron acquisition for the bacterium (115). These results are consistent with the presence of ferrous ions in the stomach, owing to its low pH and oxygen concentration. A similar situation was demonstrated in E. coli, where feo mutants were unable to colonize the mouse intestine (105). S. enterica serovar Typhimurium feoB mutants were attenuated in an animal model when mice were infected by the intragastric route but not when infection used the intraperitoneal route (111). S. enterica serovar Typhimurium feoB mutants are also outcompeted by the wild-type strain in mixed intraperitoneal infections (111).

The physiological role of the extracellular ion reductase activity of H. pylori has been proposed to be the increase of the concentration of ferrous iron, by reduction of ferric iron (121). This activity appears to depend on expression of the iron-repressed riboflavin synthesis gene ribBA (HP0804), which is involved in the production of flavin-like molecules (121), since H. pylori ribBA mutants did not display reductase activity (121). Thus, it can be hypothesized that flavins are cofactors of the reductase or directly mediate the reduction of iron. Interestingly, the H. pylori ribA and ribBA genes enable iron acquisition by E. coli strains deficient in siderophore-mediated iron uptake (7, 121). The iron reductase activity of H. pylori awaits further functional characterization and investigation of its role in colonization in animal models.

Ferric iron uptake

At mucosal surfaces, most ferric iron is complexed in heme compounds or chelated by Lf and cannot cross the OM via porins owing to their size; thus, uptake of complexed ferric iron requires active transport through both the OM and the CM. The transport systems involved in these processes have been investigated extensively in other bacteria (20, 21). In general, the iron-carrier complexes are bound first to a specific OM receptor, and there the iron ions may be removed from the iron-carrier complexes. Subsequently, iron ions are transported across the OM to the periplasm, bound to a periplasmic-binding protein and transported to an ABC transporter at the cytoplasmic membrane, which translocates the ions to the cytoplasm. Alternatively, the complete iron-carrier complex is transported through the OM, periplasm, and CM into the cytoplasm (20).

It is well established that H. pylori can use Lf, ferric citrate, heme compounds such as hemoglobin, and hemin as its sole source of iron (13, 31, 32, 58). To date, the corresponding OM transport systems have not yet been fully established. Several reports describe iron-regulated outer membrane proteins (IROMPs), but none of these proteins have been identified or characterized at the molecular level. Some IROMPs are expressed in vivo, since they are recognized by antisera from H. pylori-positive human patients (123), and therefore might be the OM receptors for these iron compounds (31, 58, 122, 123).

The H. pylori genome sequences of strains 26695 and J99 each contain six genes encoding putative IROMPs (1, 15, 108). Whereas in other gram-negative bacteria each iron compound usually requires a specific OM receptor, in H. pylori there seems to be redundancy of IROMPs as there are three genes encoding homologs of the E. coli ferric citrate receptor FecA (HP0686, HP0807, and HP1400) (20, 91) and three genes encoding homologs of the Neisseria gonorrhoeae low-affinity ferric enterobactin receptor FrpB (HP0876, HP0916/0915, and HP1512) (16). H. pylori is unable to synthesize or use the siderophore enterobactin as sole iron source (13, 58), suggesting that the FrpB homologs of this bacterium transport different iron compounds. The fact that each of the H. pylori FrpB or FecA proteins shows stronger homology with the other members of the respective H. pylori protein family than with the corresponding E. coli or N. gonorrhoeae proteins suggests that either they have slightly different substrate specificities or that one or more gene duplication events have led to the multiple copies of the frpB and fecA genes. An H. pylori fecA1 (HP0686) mutant was viable and did not show any deficiency in iron transport (115). This indicates that the FecA1 protein is not essential under in vitro growth conditions and suggests that the other two FecA homologs are able to make up for the missing FecA1 protein (115).

The OM transport process requires energy that is supplied by the TonB/ExbB/ExbD protein complex located in the CM and the periplasm (Fig. 2). This complex transfers energy from the transmembrane potential to the OM receptors. This transfer requires direct contact between TonB and the OM receptor at its TonB-binding sequence (TonB-box) located in the N terminus of the protein (65, 79). Consistent with this need is the fact that all H. pylori FecA and FrpB homologs contain putative TonB-boxes. Two TonB homologs (HP1341, HP0582) and three ExbB/ExbD couples (HP1130–1129, HP1339–1340, and HP1445–1446) were identified in the H. pylori genome sequence, again indicating redundancy in the iron transport systems. In agreement with this conclusion is the observation that an H. pylori tonB (HP1341) mutant is viable and does not show any deficiency in iron transport (115). The three ExbB/ExbD couples may be involved in the transport of different iron substrates, similar to the situation in Vibrio cholerae, which has two TonB-ExbB-ExbD sets that interact with different OM receptors (86). Although H. pylori cannot synthesize or use enterobactin, the genes HP1561 and HP1562 encode putative iron-transporting periplasmic binding proteins with low homology to the CeuE enterobactin transport protein of Campylobacter jejuni (95).

The final transport step of iron or iron compounds across the CM usually is mediated by an ABC transporter. Such systems consist generally of one or two cytoplasmic membrane permeases and one or two ATP-hydrolyzing proteins (ATPases), which form the conduit in the membrane and supply the necessary energy, respectively. In contrast to the multitude of putative OM receptor genes present in the H. pylori genome, only one gene encoding an ABC transport system for iron could be identified. This system consists of the permease FecD (HP0889) and the ATPase FecE (HP0888), which are homologous to components of the E. coli ferric citrate transport system, e.g., the FecA proteins (20, 91). The H. pylori fecD and fecE genes are adjacent in the genome and are probably cotranscribed. An H. pylori fecDE mutant was not affected in its iron transport capability, manifesting the redundancy of ferric iron transport systems in the bacterium (115). The fecDE genes are located downstream of the vacA gene encoding the vacuolating cytotoxin, which has been proposed to be regulated by iron (107), although a link between VacA production and iron uptake has not been described yet. In conclusion, the presence of seven putative iron uptake systems indicates the importance of iron acquisition for H. pylori.

Potassium Transport

Potassium is the major cation in the bacterial cytoplasm, found at concentrations up to 0.5 M even when extracellular levels are very low (100). Potassium is also the main cation involved in osmoregulation and maintenance of the osmotic pressure (28). In E. coli several systems that maintain potassium homeostasis have been identified. These include constitutive low-affinity importers and inducible high-affinity importers and exporters. The latter allow the cell to respond to changes in the extracellular potassium levels (28, 100).

Low-affinity, high-rate potassium importers of gram-negative bacteria such as E. coli consist of the two Trk transporters and the Kup system, whereas high-affinity low-rate potassium transport is mediated by the Kdp system (100). Surprisingly, none of these systems is present in H. pylori, and how H. pylori acquires potassium remains unknown. It is possible that potassium enters the cell through other, yet unidentified importers or through nonspecific channels. The gene HP0490 encodes a protein with low homology to bacterial orthologs of eukaryotic potassium channels. Eukaryotic channels allow rapid and nonspecific passage of cations through the membrane in a single event (28). However, such a system can be expected to be insufficient to cater to cellular demands for potassium, and it is likely that H. pylori has other potassium uptake systems.

Two highly similar potassium efflux proteins have been identified in E. coli, the KefB and KefC proteins, which mediate removal of excess potassium by acting as potassium-proton antiporters (100). H. pylori contains only a single gene (HP0471), encoding a Kef homolog, which is most closely related to KefB.

Sodium Transport

The intracellular sodium concentration of bacteria is usually lower than that of the environment. This is mostly achieved by the export of sodium ions by sodium-proton antiporters (Fig. 2). These transporters assist in maintaining intracellular pH, osmolarity, and salt concentration (100). The H. pylori nhaA gene (HP1552) encodes a homolog of a sodium-proton antiporter. This gene is able to complement an E. coli mutant lacking all sodium-proton antiporter activity (60). An interesting difference between E. coli and H. pylori NhaA is their respective activities at different pH values. H. pylori NhaA shows high activity at pH values between 6 and 8.5, while E. coli NhaA is only active above pH 8. The activity of H. pylori NhaA at higher proton concentrations may reflect an adaptation to the acidic conditions in the gastric mucosa. It was recently postulated that a stretch of 40 extra amino acids that is only present in H. pylori NhaA might mediate its altered pH sensitivity (60). H. pylori contains a second gene (HP1183) encoding a putative sodium-proton antiporter homolog as well as four homologs of transport systems that probably use sodium as symport or counterport ion, namely, the sodium-glutamate (HP1506), sodium-proline (HP0055), and sodium-alanine (HP0942) symporters and l-serine permease (HP0133).

Magnesium Transport

Bacteria require micromolar concentrations of magnesium for growth, and thus have the need for active magnesium acquisition. Magnesium uptake has been extensively studied in S. enterica serovar Typhimurium, which contains four magnesium transport systems, the CorA, MgtA, MgtB, and MgtE transporters (102), of which only a CorA homolog (HP1344) is present in H. pylori. CorA homologs are found in almost all microbial genomes analyzed so far and are thought to be ubiquitous in the eubacteria (102). S. enterica serovar Typhimurium CorA can mediate both import and export of magnesium, cobalt, and nickel (102). It has also been implicated to transport ferrous iron (51). However, the affinity of S. enterica serovar Typhimurium CorA for magnesium is much higher than for cobalt and nickel (102). The role of the H. pylori CorA homolog in cation transport has not been investigated experimentally, and its cation specificity may well differ from that of its eubacterial homologs.

Trace Metal Transport

In most gram-negative bacteria, transmembrane ion import via transport proteins like NixA or CorA occurs with relatively little ion specificity, although with different affinities (42, 102). Some metals might enter the cell also through phosphate or other ion transporters. Bacteria require small amounts of transition metals like cobalt or copper, but when present at higher concentrations, these metals are toxic (10, 56, 101). Other transition metals like cadmium are toxic even at very low concentrations. To keep the concentration of these cations below toxic levels, bacteria require efflux systems next to uptake systems. This is especially important for H. pylori, as the enzymatic activity of its urease is very sensitive to transition metals (89).

Metal resistance in bacteria is predominantly achieved by specific P-type ATPases such as CopA (101), and/or by multicomponent cation-proton antiporters as the R. eutropha CzcABC system (101). Analyses of the H. pylori genome sequences indicate the presence of genes encoding both types of metal resistance systems. Three H. pylori P-type ATPases have been identified so far, and two of them, CadA and CopA, have been characterized experimentally.

The cadmium-zinc-cobalt efflux pump CadA

The H. pylori protein CadA encoded by gene HP0791 was originally cloned by hybridization screening for the conserved phosphorylation motif of P-type ATPases (72). The protein sequence is homologous to other bacterial cadmium and copper P-type ATPases and contains eight transmembrane domains (71, 72). Mutational studies demonstrated that CadA is involved in resistance to cadmium, zinc, and cobalt, but not to copper or nickel, indicating that this exporter is not specific for a single metal (56). Inactivation of cadA also reduced urease activity and nickel accumulation in some but not all the mutants (56), but the reduced urease activity was not related directly to the disruption of cadA, and the exact role of CadA in metal and urease metabolism remains to be determined (56).

The copper efflux pump CopA

The H. pylori copper resistance determinant consists of two genes, copA (HP1072) and copP (HP1073) (5, 6, 46, 47, 70). The protein CopA is a P-type ATPase, exports copper ions, and is homologous to other copper-transporting enzymes. CopA is predicted to have eight transmembrane domains, similar to CadA (72). Insertional mutagenesis of copA made H. pylori significantly more sensitive to copper, but the resistance to cadmium, mercury, nickel, calcium, and magnesium was not affected (5, 6, 46, 47). CopP is a homolog of the Enterococcus hirae CopZ protein (26). CopZ-like proteins are copper-chaperones, delivering copper to enzymes and regulators (26, 53). As mutation of copP did not alter copper sensitivity, the role of CopP in copper metabolism of H. pylori remains unclear. Possible functions of CopP are storage of copper (analogous to iron storage by ferritin) or chaperone activity like that of CopZ (26, 53).

Other cation efflux systems

In addition to cadA and copA, H. pylori contains genes for three other putative cation efflux systems: HP1503 encoding a third P-type ATPase, designated CopA2 or FixI, and HP0969/0970 and HP1329/1328, part of an incomplete czc multicomponent system. Czc cation-efflux systems are cation-proton antiporters and usually contain a CM transporter (CzcA), a periplasm-spanning protein (CzcB), and an OM protein thought to be involved in transport across the OM (CzcC) (101). There are two separate loci encoding CzcA and CzcB homologs, but a CzcC homolog has not been identified in the H. pylori genome sequences. Experimental evidence for any of these systems being involved in cation transport is not available yet. Mutation of czcA gene HP0969 resulted in an acid-sensitive phenotype, suggesting a role for the CzcA protein in acid tolerance (18), although the mechanism for the acid-sensitive phenotype of the czcA mutant is not known.

Molybdate transport

Molybdenum is an essential trace element for all bacteria, and molybdoenzymes play a central role, especially in anaerobic metabolism (36). Molybdenum is transported in the molybdate form (MoO42−) by an ABC transporter system consisting of the ModA periplasmic binding protein, the ModB CM permease, and the ModC ATPase (36, 50). In E. coli, the mod locus also contains three additional genes, which encode the ModE regulatory protein and two proteins, ModD and ModF, of unknown function (50). H. pylori contains genes encoding ModA (HP0473), ModB (HP0474), and ModC (HP0475) homologs, but genes ortholog to those encoding the regulator ModE as well as ModD and ModF homologs have not been found.


During coevolution with the host, H. pylori has developed unique systems necessary for survival in the human stomach. Concerning competition for nutrients as well as the acidic pH, this niche differs considerably from the environments most other bacteria colonize. Elements of its systems for ion metabolism and transport seem to reflect specific adaptations of H. pylori to its ecological niche, and the functions and mechanisms involved might be different from the paradigms developed for enteric bacteria like E. coli.

H. pylori contains relatively low numbers of ion transport systems, except for nickel and iron. These two ions can be transported by two or more systems, indicating their importance in the physiology of H. pylori. The number of regulatory proteins involved in ion metabolism and uptake is also low, and those that have been identified seem to be involved in the regulation of nickel and iron homeostasis. This is surprising, as the gastric mucosa where H. pylori resides is a challenging environment, in which conditions can vary considerably. Thus, it is possible to infer that systems contributing to ion homeostasis in H. pylori have an extra level of functionality. Further insights into the mechanisms governing ion homeostasis might allow the development of new or improved strategies to prevent or cure infection of this versatile pathogen.


We thank our present and past collaborators for their valuable suggestions and helpful discussions and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO grant 901-14-206) and the Deutsche Forschungsgemeinschaft (DFG grants Ki201/8-1, Ki201/8-2, and Ki201/9-1) for financial support.


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