Yeasts take up iron by three main mechanisms. In the reductive uptake mechanism, specialized flavo-hemoproteins (Fre) dissociate extracellular ferric complexes by reduction involving trans-plasma membrane electron transfer. The resulting free iron is then imported by a high-affinity permease system (Ftr), coupled to a copper-dependent oxidase (Fet), which channels iron through the plasma membrane. As a consequence, iron uptake by this mechanism is dependent on the availability of copper. In the siderophore-mediated mechanism, siderophores excreted by the cells or produced by other bacterial or fungal species are taken up without prior dissociation, via specific, copper-independent high-affinity receptors. The iron is then dissociated from the siderophores intracellularly, probably by reduction. In the heme uptake mechanism, free heme or heme bound to hemoglobin is taken up as such, probably by endocytosis. Iron is released intracellularly after hydrolysis of the porphyrin ring catalyzed by heme oxygenase. Within the cell, iron is stored in vacuoles or in siderophores.

Iron can be mobilized from vacuoles by a reductive mechanism homologous to that found at the plasma membrane. Regulation of iron uptake and iron use are mediated by transcriptional regulators acting either as activators in iron-deficient conditions or as repressors in iron-rich conditions, according to the yeast species; these regulators thus adjust the iron uptake flux to the cell's requirements. In the baker's yeast, Saccharomyces cerevisiae, a post-transcriptional mechanism is active under low iron conditions, involving the degradation of RNAs encoding inessential iron-utilizing proteins. Other fungi have mechanisms serving a similar purpose at the transcriptional level. Studies in S. cerevisiae show that mitochondria are central to regulating cellular iron homeostasis, through the synthesis of iron-sulfur clusters.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: fungal, fungi, Iron acquisition mechanisms, Iron transporters, Iron uptake in Yeasts, Iron uptake systems, Iron-homeostasis, Iron-uptake, mycology, Siderophores, yeast, Yeasts

Staphylococcus aureus causes a significant amount of human morbidity and mortality. The ability of S. aureus to cause disease is dependent upon its acquisition of iron from the host. S. aureus can obtain iron from various sources during infection, including heme and transferrin. The most abundant iron source in humans is heme-iron bound by hemoglobin contained within erythrocytes. S. aureus is known to lyse erythrocytes through secretion of pore-forming toxins, providing access to host hemoglobin.

Proteins of the iron-regulated surface determinant (Isd) system bind host hemoproteins, remove the heme cofactor, and shuttle heme into the cytoplasm for use as a nutrient iron source. Deletion of Isd system components decreases staphylococcal virulence, underscoring the importance of heme-iron acquisition during infection. In addition to heme, S. aureus can utilize transferrin-iron through the secretion of siderophores. Several staphylococcal siderophores have been described, some of which have defined roles during the pathogenesis of staphylococcal infections. A greater understanding of staphylococcal iron acquisition may lead to the development of novel therapeutic strategies that target nutrient uptake and decrease the threat of this increasingly drug-resistant bacterial pathogen.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: Heme, Heme uptake, Iron acquisition mechanisms, Iron transporters, Iron uptake in Staphylococci, Iron uptake systems, Iron-homeostasis, Iron-uptake, Siderophore, Siderophores, Staphylococci

Bacillus subtilis is a metabolically versatile soil microbe and Gram-positive model organism that displays a sophisticated adaptive response to conditions of iron limitation. The endogenous siderophore of B. subtilis is bacillibactin, a trimeric catecholate siderophore similar in structure to enterobactin. In addition to bacillibactin, B. subtilis can obtain iron from several xenosiderophores, ferric citrate, heme, and through a newly discovered elemental iron permease.

The regulation of iron homeostasis in B. subtilis is complex and involves a ferric uptake regulator (Fur) protein as master regulator and at least two subsidiary regulatory systems. The most significant of these is an iron-sparing/prioritization response controlled by the small RNA FsrA and three auxiliary proteins (FbpABC). In addition, the bacillibactin uptake system is transcriptionally activated by an AraC family activator, Btr that directly senses bacillibactin. Iron uptake and homeostasis systems in B. anthracis and related organisms are largely similar to those in B. subtilis with some additional components. These include a second siderophore synthesis operon for petrobactin, which is important for virulence, and a more elaborate (or at least better understood) heme uptake system.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: bacillus, Iron acquisition mechanisms, Iron deficiency, Iron transporters, Iron uptake in Bacillus, Iron uptake systems, Iron-homeostasis, Iron-uptake, Siderophore, Siderophores

Cyanobacteria are dependent on but can also be compromised by metals such as iron. On the one hand the demand for iron for photosystem functionality represents a challenge for the iron uptake machinery in iron limiting environments. On the other hand intoxication by iron causes a severe problem for growth and reproduction. To overcome this dilemma cyanobacteria have developed a regulatory network controlling iron uptake. They produce siderophores, which are distinct from that of other bacteria. Furthermore, the iron metabolism is linked to the nitrogen metabolism as documented for example in Anabaena sp. PCC 7120.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: Anabaena, cyanobacteria, Iron acquisition mechanisms, Iron deficiency, Iron transporters, Iron uptake in Cyanobacteria, Iron uptake systems, Iron-homeostasis, Iron-uptake, Siderophore, Siderophores

Iron is known to catalyze a wide range of biochemical reactions essential for most living organisms, including Campylobacter jejuni. Paradoxically, this iron reactivity is also responsible for the generation of hydroxyl radicals (·OH), which are particularly biotoxic. In order to avoid iron toxicity, microorganisms must achieve an effective iron homeostasis by tightly regulating the expression of genes encoding the proteins involved in iron acquisition, metabolism and oxidative stress defences in response to iron availability. Interestingly, in addition to the classical ferric uptake regulator Fur, C. jejuni carries another member of the Fur family of metalloregulators, PerR. PerR is a peroxide-sensing regulator and typically regulates peroxide stress response in Gram-positive bacteria. Recent work indicates that the regulatory functions of Fur and PerR extend beyond their classically ascribed roles. These diverse functions include energy metabolism, protein glycosylation and flagella biogenesis. Moreover, the Fur and PerR regulons appear to overlap and co-regulate key genes at specific junctions.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: Campylobacter, Iron acquisition mechanisms, Iron transporters, Iron uptake in Campylobacter, Iron uptake systems, Iron-homeostasis, Iron-metabolism, Iron-uptake

Bacteroides spp. have an essential requirement for heme and non-heme iron. They cannot synthesize the tetrapyrrole macrocycle ring due to a lack of genes for the heme biosynthetic pathway. It is remarkable that heme-dependent organisms outnumber heme-independent organisms in the lower intestinal tract suggesting that heme biosynthesis is not essential for colonization of the colonic environment. However, this colonization advantage may be due to the fact that under anaerobic conditions in the presence of heme, B. fragilis can generate nearly the double amount of ATP than Escherichia coli per mol of glucose. This high energy yield is linked to a rudimentary heme-induced fumarate reductase and cytochrome b-dependent electron transport energy metabolism pathway which uses fumarate as the terminal electron acceptor. Moreover, Bacteroides spp. can incorporate iron-deuteroporphyrin and iron-mesoporphyrin into a functional type-b cytochrome. Heme can be demetalated without cleaving the tetrapyrrole ring releasing free iron and free protoporphirin IX. The ability of the opportunistic human pathogen B. fragilis to cause infections seems to be due in part to its ability to scavenge heme and iron from host proteins. The in-frame translated intergenic region of the fused FeoAB proteins are exclusively present in gastro-intestinal colonizers belonging to the Bacteroidetes, Firmicutes and Actinobacteria phyla. Several members of the Bacteroides group have three orthologs of the mammalian-type bacterial ferritin gene, ftnA. FtnA may play an important role in protection against iron-induced oxidative stress in this group of highly aerotolerant anaerobes.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: Bacteroides, Iron acquisition mechanisms, Iron transporters, Iron uptake in Bacteroides, Iron uptake systems, Iron-homeostasis, Iron-metabolism, Iron-uptake

Francisella tularensis is unusual among Gram-negative bacteria in that its genome does not encode orthologs for TonB, ExbB and ExbD that typically energize the uptake of iron across the outer membrane. This organism secretes however a siderophore similar in structure to rhizoferrin. The fsl operon of six genes encodes functions for biosynthesis and uptake of the siderophore. Two of these genes encode a siderophore synthetase belonging to the nonribosomal peptide synthetase (NRPS)-independent synthetase (NIS)-family and a protein belonging to the pyridoxyl phosphate-dependent decarboxylase family, and both are required for siderophore production. Siderophore utilization involves the product of the fslE gene, a protein unique to Francisella species that could function as a siderophore receptor. Additionally, genes related in sequence to fslE also play a role in siderophore acquisition. The mechanism for TonB-independent iron uptake in this microorganism remains to be elucidated.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: Francisella, Iron acquisition mechanisms, Iron transporters, Iron uptake in Francisella, Iron uptake systems, Iron-homeostasis, Iron-metabolism, Iron-uptake

Upon colonization of the mammalian respiratory epithelium by mucosal pathogens of the genus Bordetella, the host-pathogen interaction causes inflammatory changes, immune activation, and host cell injury. In this dynamic environment, Bordetella cells scavenge the nutritional iron necessary for growth. The three classical Bordetella species produce the siderophore alcaligin. In addition, they can utilize xenosiderophores that could be produced by commensals or other microbes that transiently inhabit the nasopharynx.

As infection progresses, extravasation of immune cells, erythrocytes and serum to the mucosal surface can occur, exacerbated by the damaging action of Bordetella toxins, thus providing iron sources such as transferrin and heme compounds to the microbe. The three characterized Bordetella iron systems for utilization of alcaligin, enterobactin and heme are each inducible by the cognate iron source. The ability to sense and respond to the presence of available iron sources allows these pathogens to adapt to temporal changes in iron source availability, and this ability is important for successful in vivo growth.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: Bordetella, Iron acquisition mechanisms, Iron deficiency, Iron extraction, Iron transporters, pertussis, Siderophore, Siderophores

Iron is essential for almost all living organisms as it is involved in a wide variety of important metabolic processes. However, iron is not readily available and microorganisms therefore employ various iron uptake systems to secure sufficient supplies from their surroundings. There is considerable variation in the range of iron transporters and iron sources utilised by different microbial species. Pathogens, in particular, require efficient iron acquisition mechanisms to enable them to compete successfully for iron in the highly iron-restricted environment of the host's tissues and body fluids.

Further reading: Iron Uptake and Homeostasis in Microorganisms

Labels: Iron acquisition mechanisms, Iron transporters, Iron uptake systems, Iron-homeostasis, Iron-metabolism, Iron-uptake