Specificity of Metal Sensing: Iron and Manganese Homeostasis in Bacillus subtilis

Abstract

Metalloregulatory proteins allow cells to sense metal ions and appropriately adjust the expression of metal uptake, storage, and efflux pathways. Bacillus subtilis provides a model for the coordinate regulation of iron and manganese homeostasis that involves three key regulators: Fur senses iron sufficiency, MntR senses manganese sufficiency, and PerR senses the intracellular Fe/Mn ratio. Here, I review the structural and physiological bases of selective metal perception, the effects of non-cognate metals, and mechanisms that may serve to coordinate iron and manganese homeostasis. Manganese and Iron: Chemically Similar Elements with Distinct Roles in Cell PhysiologyManganese and iron are both predominantly present as divalent cations in the reducing environment of the cytoplasm and are maintained at overall concentrations (averaged over the cell) that can approach 0.5 mM (1-3). Much of this manganese and iron is bound by enzymes that acquire metal from a kinetically accessible (labile) pool buffered in the low M range (4 -6). These two metals are not only important from the perspective of individual microbial cells, but have a global impact due to their central roles in photosynthesis, nitrogen fixation, and other key steps in elemental cycling.Nearly all cellular life requires significant amounts of iron. The sole documented exceptions are the lactobacilli and the spirochete Borrelia burgdorferi, which have little if any requirement for iron (3). Coincident with this disregard for iron, these same organisms have high requirements for manganese and have been described as manganese-centric (7). Conversely, other organisms have little demonstrable requirement for manganese, although they may use manganese when available. The best characterized is Escherichia coli, which has a largely ironcentric metabolism, but conditionally imports manganese in response to oxidative stress (8).Here, I review the key factors regulating iron and Mn homeostasis in the model organism Bacillus subtilis. B. subtilis encodes three members of the Fur 2 family (Fur, PerR, and Zur) and one member of the DtxR/MntR family (MntR) that regulate the import of nutrient metal ions (9 -11). Structural and biochemical studies have provided insights into the mechanisms of selective activation of these repressors by their cognate metal ions (12-14). B. subtilis requires both iron and manganese for growth, a property shared with many pathogens for which the ability to obtain these metals from the host is a critical determinant of virulence (7,(15)(16)(17). Metalloregulators as a Window into Cellular PhysiologyMetalloregulators function as the arbiters of metal ion sufficiency and excess (6,12,18). For those that sense sufficiency, the affinity (measured as K d ) for their cognate metal(s) defines the level of metal judged to be sufficient. When free metal concentrations rise above this level, the regulator transitions from its inactive (apo-) form to its activated (holo-) form and represses expression of metal import. In B. subtilis, Fur serves as ...

Discrete Responses to Limitation for Iron and Manganese in Agrobacterium tumefaciens: Influence on Attachment and Biofilm Formation

“…Several reports suggest overlapping and integrated responses to environmental iron and manganese levels (2,8,11,65,66,77). Our data argue against such integration at the level of transcription in A. tumefaciens.…”

“…We have previously described the regulatory system governing the response of A. tumefaciens to iron, and a growing body of evidence suggests that the manganeseresponsive regulatory system is functionally connected to that of iron in a broad spectrum of bacteria (2,8,24,65,66). A. tumefaciens has predicted homologues of two different manganese uptake systems, the ABC transporter sitABCD (Atu4471 to Atu4468) and the Nramp1 Mn 2ϩ /H ϩ symporter mntH (Atu1736) (19,20), and both of these were upregulated under manganese limitation.…”

“…Both of these metals play roles in a wide range of cellular processes, including energy generation, sugar and amino acid metabolism, and oxidative stress resistance (1)(2)(3). The metal-responsive systems of the alphaproteobacteria are often divergent from those of other bacterial groups (4).…”

Structure–function analysis of manganese exporter proteins across bacteria

“…Over-accumulation of manganese is often correlated with deficiencies in other metal pools. This can then cause mis-metallation of regulatory transcription factors and key enzymes, affecting growth, sensitivity to ROS, and virulence (3,6,(15)(16)(17)(18). For example, in E. coli, excess intracellular manganese results in aberrantly low levels of iron through the action of Mn-Fur, which shuts down iron uptake.…”

Comparative Genomics of DtxR Family Regulons for Metal Homeostasis in Archaea

“…Many transition metals are taken up by specific transport systems, including FeoAB family transporters for ferrous iron (1,2), Fbp-type ATP-binding cassette (ABC) transporters for ferric iron (3), Znu family ABC transporters for zinc (4), and NRAMP family MntR transporters for manganese (5). The precise maintenance of metal ion homeostasis, including metal uptake transporters, is vital for cells that have to balance between supplying enzymes with metal ion cofactors and decreasing the harmful effects of heavy metals (6,7).…”