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  • 1
    Language: English
    In: Journal of bacteriology, April 2014, Vol.196(7), pp.1335-42
    Description: The reactive nature of heme enables its use as an enzymatic cofactor while rendering excess heme toxic. The importance of heme detoxification machinery is highlighted by the presence of various types of these homeostatic systems in Gram-positive and Gram-negative microorganisms. A number of pathogens possess orthologs of the HssRS/HrtAB heme detoxification system, underscoring a potential role this system plays in the survival of bacteria in heme-rich environments such as the vertebrate host. In this work, we sought to determine the role of this system in protection against metalloporphyrin heme analogues identified by previous studies as antimicrobial agents. Our findings demonstrate that only toxic metalloporphyrins maximally activate expression of the Staphylococcus aureus heme detoxification system, suggesting that the sensing mechanism of HssRS might require a component of the associated toxicity rather than or in addition to the metalloporphyrin itself. We further establish that only a subset of toxic metalloporphyrins elicit the oxidative damage previously shown to be a significant component of heme toxicity whereas all toxic noniron metalloporphyrins inhibit bacterial respiration. Finally, we demonstrate that, despite the fact that toxic metalloporphyrin treatment induces expression of S. aureus heme detoxification machinery, the HrtAB heme export pump is unable to detoxify most of these molecules. The ineffectiveness of HrtAB against toxic heme analogues provides an explanation for their increased antimicrobial activity relative to heme. Additionally, these studies define the specificity of HssRS/HrtAB, which may provide future insight into the biochemical mechanisms of these systems.
    Keywords: Gene Expression Regulation, Bacterial ; Bacterial Proteins -- Metabolism ; Heme -- Metabolism ; Staphylococcal Infections -- Microbiology ; Staphylococcus Aureus -- Metabolism
    ISSN: 00219193
    E-ISSN: 1098-5530
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  • 2
    Language: English
    In: Journal of Bacteriology, 2014, Vol.196(5-6), p.1206(9)
    Description: Magnesium is the most abundant divalent metal in cells and is required for many structural and enzymatic functions. For bacteria, at least three families of proteins function as magnesium transporters. In recent years, it has been shown that a subset of these transport proteins is regulated by magnesium-responsive genetic control elements. In this study, we investigated the cellular requirements for magnesium homeostasis in the model microorganism Bacillus subtilis. Putative magnesium transporter genes were mutationally disrupted, singly and in combination, in order to assess their general importance. Mutation of only one of these genes resulted in strong dependency on supplemental extracellular magnesium. Notably, this transporter gene, mgtE, is known to be under magnesium-responsive genetic regulatory control. This suggests that the identification of magnesium-responsive genetic mechanisms may generally denote primary transport proteins for bacteria. To investigate whether B. subtilis encodes yet additional classes of transport mechanisms, suppressor strains that permitted the growth of a transporter-defective mutant were identified. Several of these strains were sequenced to determine the genetic basis of the suppressor phenotypes. None of these mutations occurred in transport protein homologues; instead, they affected housekeeping functions, such as signal recognition particle components and ATP synthase machinery. From these aggregate data, we speculate that the mgtE protein provides the primary route of magnesium import in B. subtilis and that the other putative transport proteins are likely to be utilized for more-specialized growth conditions.
    Keywords: Bacillus Subtilis – Research ; Bacillus Subtilis – Physiological Aspects ; Magnesium Compounds – Physiological Aspects ; Magnesium Compounds – Research ; Transport Proteins – Research
    ISSN: 0021-9193
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: J. Mol. Biol, 09 December 2011, Vol.407((4) ; 04, 2011)
    Description: The M-box riboswitch couples intracellular magnesium levels to expression of bacterial metal transport genes. Structural analyses on other riboswitch RNA classes, which typically respond to a small organic metabolite, have revealed that ligand recognition occurs through a combination of base-stacking, electrostatic, and hydrogen-bonding interactions. In contrast, the M-box RNA triggers a change in gene expression upon association with an undefined population of metals, rather than responding to only a single ligand. Prior biophysical experimentation suggested that divalent ions associate with the M-box RNA to promote a compacted tertiary conformation, resulting in sequestration of a short sequence tract otherwise required for downstream gene expression. Electrostatic shielding from loosely associated metals is undoubtedly an important influence during this metal-mediated compaction pathway. However, it is also likely that a subset of divalent ions specifically occupies cation binding sites and promotes proper positioning of functional groups for tertiary structure stabilization. To better elucidate the role of these metal binding sites, we resolved a manganese-chelated M-box RNA complex to 1.86 {angstrom} by X-ray crystallography. These data support the presence of at least eight well-ordered cation binding pockets, including several sites that had been predicted by biochemical studies but were not observed in prior structural analysis. Overall, these data support the presence of three metal-binding cores within the M-box RNA that facilitate a network of long-range interactions within the metal-bound, compacted conformation.
    Keywords: Basic Biological Sciences ; 60 Applied LIFE Sciences ; Cations ; Crystallography ; Electrostatics ; Functionals ; Genes ; Interaction Range ; Magnesium ; Positioning ; RNA ; Shielding ; Stabilization ; Transport ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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  • 4
    Language: English
    In: Journal of bacteriology, 2014, Vol.196(6), pp.1206-1214
    Description: Magnesium is the most abundant divalent metal in cells and is required for many structural and enzymatic functions. For bacteria, at least three families of proteins function as magnesium transporters. In recent years, it has been shown that a subset of these transport proteins is regulated by magnesium-responsive genetic control elements. In this study, we investigated the cellular requirements for magnesium homeostasis in the model microorganism Bacillus subtilis. Putative magnesium transporter genes were mutationally disrupted, singly and in combination, in order to assess their general importance. Mutation of only one of these genes resulted in strong dependency on supplemental extracellular magnesium. Notably, this transporter gene, mgtE, is known to be under magnesium-responsive genetic regulatory control. This suggests that the identification of magnesium-responsive genetic mechanisms may generally denote primary transport proteins for bacteria. To investigate whether B. subtilis encodes yet additional classes of transport mechanisms, suppressor strains that permitted the growth of a transporter-defective mutant were identified. Several of these strains were sequenced to determine the genetic basis of the suppressor phenotypes. None of these mutations occurred in transport protein homologues; instead, they affected housekeeping functions, such as signal recognition particle components and ATP synthase machinery. From these aggregate data, we speculate that the mgtE protein provides the primary route of magnesium import in B. subtilis and that the other putative transport proteins are likely to be utilized for more-specialized growth conditions. ; p. 1206-1214.
    Keywords: H-Transporting Atp Synthase ; Magnesium ; Transporters ; Bacillus Subtilis ; Genes ; Bacteria ; Mutation ; Homeostasis ; Phenotype ; Bacteriology ; Mutants
    ISSN: 0021-9193
    Source: AGRIS (Food and Agriculture Organization of the United Nations)
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  • 5
    Language: English
    In: Current Opinion in Microbiology, April 2012, Vol.15(2), pp.169-174
    Description: ► Pathogenic organisms encounter metal stresses in the host environment. ► Pathogens alter their physiology to accommodate iron restriction within the host. ► Copper excess within the host induces multiple forms of toxicity in bacteria. Owing to the unique redox potential of transition metals, many of these elements serve important roles as cofactors in numerous enzymes. However, the reactive nature of metal becomes an intracellular threat when these ions are present in excess. Therefore, all organisms require mechanisms for sensing small fluctuations in metal levels to maintain a controlled balance of uptake, efflux, and sequestration. The ability to sense metal ion concentration is especially important for the survival of pathogenic bacteria because host organisms can both restrict access to essential metals from invading pathogens and utilize the innate toxicity of certain metals for bacterial killing. Host-induced metal ion fluctuations must be rapidly sensed by pathogenic bacteria so that they can activate metal transport systems, alter their physiology to accommodate differences in metal concentrations, and regulate the expression of virulence factors.
    Keywords: Biology
    ISSN: 1369-5274
    E-ISSN: 1879-0364
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  • 6
    In: Molecular Microbiology, December 2012, Vol.86(6), pp.1376-1392
    Description: is a pathogen that infects multiple anatomical sites leading to a diverse array of diseases. Although vertebrates can restrict the growth of invading pathogens by sequestering iron within haem, surmounts this challenge by employing high‐affinity haem uptake systems. However, the presence of excess haem is highly toxic, necessitating tight regulation of haem levels. To overcome haem stress, expresses the detoxification system . In this work, a transposon screen was performed in the background of a haem‐susceptible, ‐deficient strain to identify the substrate transported by this putative pump and the source of haem toxicity. While a recent report indicates that exports haem itself, the haem‐resistant mutants uncovered by the transposon selection enabled us to elucidate the cellular factors contributing to haem toxicity. All mutants identified in this screen inactivated the menaquinone () biosynthesis pathway. Deletion of the final steps of this pathway revealed that quinone molecules localizing to the cell membrane potentiate haem‐associated superoxide production and subsequent oxidative damage. These data suggest a model in which membrane‐associated haem and quinone molecules form a redox cycle that continuously generates semiquinones and reduced haem, both of which react with atmospheric oxygen to produce superoxide.
    Keywords: Biology;
    ISSN: 0950-382X
    E-ISSN: 1365-2958
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  • 7
    Language: English
    In: Journal of Molecular Biology, 25 September 2009, Vol.392(3), pp.723-735
    Description: Riboswitches are regulatory RNAs that control downstream gene expression in response to direct association with intracellular metabolites or metals. Typically, riboswitch aptamer domains bind to a single small-molecule metabolite. In contrast, an X-ray crystallographic structural model for the M-box riboswitch aptamer revealed the absence of an organic metabolite ligand but the presence of at least six tightly associated magnesiums. This observation agrees well with the proposed role of the M-box riboswitch in functioning as a sensor of intracellular magnesium, although additional nonspecific metal interactions are also undoubtedly required for these purposes. To gain greater functional insight into the metalloregulatory capabilities of M-box RNAs, we sought to determine whether all or a subset of the RNA-chelated magnesium ions were required for riboswitch function. To accomplish this task, each magnesium-binding site was simultaneously yet individually perturbed through random incorporation of phosphorothioate nucleotide analogues, and RNA molecules were investigated for their ability to fold in varying levels of magnesium. These data revealed that all of the magnesium ions observed in the structural model are important for magnesium-dependent tertiary structure formation. Additionally, these functional data revealed a new core of potential metal-binding sites that are likely to assist formation of key tertiary interactions and were previously unobserved in the structural model. It is clear from these data that M-box RNAs require specific binding of a network of metal ions for partial fulfillment of their metalloregulatory functions.
    Keywords: Nucleotide Analogue Interference Mapping ; Noncoding RNA ; Riboswitch ; Magnesium–RNA Interaction ; RNA Folding ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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  • 8
    Language: English
    In: Journal of bacteriology, March 2014, Vol.196(6), pp.1206-14
    Description: Magnesium is the most abundant divalent metal in cells and is required for many structural and enzymatic functions. For bacteria, at least three families of proteins function as magnesium transporters. In recent years, it has been shown that a subset of these transport proteins is regulated by magnesium-responsive genetic control elements. In this study, we investigated the cellular requirements for magnesium homeostasis in the model microorganism Bacillus subtilis. Putative magnesium transporter genes were mutationally disrupted, singly and in combination, in order to assess their general importance. Mutation of only one of these genes resulted in strong dependency on supplemental extracellular magnesium. Notably, this transporter gene, mgtE, is known to be under magnesium-responsive genetic regulatory control. This suggests that the identification of magnesium-responsive genetic mechanisms may generally denote primary transport proteins for bacteria. To investigate whether B. subtilis encodes yet additional classes of transport mechanisms, suppressor strains that permitted the growth of a transporter-defective mutant were identified. Several of these strains were sequenced to determine the genetic basis of the suppressor phenotypes. None of these mutations occurred in transport protein homologues; instead, they affected housekeeping functions, such as signal recognition particle components and ATP synthase machinery. From these aggregate data, we speculate that the mgtE protein provides the primary route of magnesium import in B. subtilis and that the other putative transport proteins are likely to be utilized for more-specialized growth conditions.
    Keywords: Antiporters -- Metabolism ; Bacillus Subtilis -- Metabolism ; Bacterial Proteins -- Metabolism ; Magnesium -- Metabolism
    ISSN: 00219193
    E-ISSN: 1098-5530
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  • 9
    Language: English
    In: Cell, 2007, Vol.130(5), pp.878-892
    Description: Organisms maintain the correct balance of intracellular metals primarily through metal-sensing proteins that control transport and storage of the target ion(s). Here, we reveal the basis of metal sensing and genetic control by a metalloregulatory RNA. Our data demonstrate that a previously uncharacterized orphan riboswitch, renamed the “M-box,” is a divalent metal-sensing RNA involved in Mg homeostasis. A combination of genetic, biochemical, and biophysical techniques demonstrate that Mg induces a compacted tertiary architecture for M-box RNAs that regulates the accessibility of nucleotides involved in genetic control. Molecular details are provided by crystallographic structure determination of a Mg -bound M-box RNA. Given the distribution of this RNA element, it may constitute a common mode for bacterial metal ion regulation, and its discovery suggests the possibility of additional RNA-based metal sensors in modern and primordial organisms.
    Keywords: Cellbio ; RNA ; Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 10
    Language: English
    In: 2014, Vol.10(6), p.e1004429
    Description: Magnesium is an essential divalent metal that serves many cellular functions. While most divalent cations are maintained at relatively low intracellular concentrations, magnesium is maintained at a higher level (∼0.5–2.0 mM). Three families of transport proteins were previously identified for magnesium import: CorA, MgtE, and MgtA/MgtB P-type ATPases. In the current study, we find that expression of a bacterial protein unrelated to these transporters can fully restore growth to a bacterial mutant that lacks known magnesium transporters, suggesting it is a new importer for magnesium. We demonstrate that this transport activity is likely to be specific rather than resulting from substrate promiscuity because the proteins are incapable of manganese import. This magnesium transport protein is distantly related to the Nramp family of proteins, which have been shown to transport divalent cations but have never been shown to recognize magnesium. We also find gene expression of the new magnesium transporter to be controlled by a magnesium-sensing riboswitch. Importantly, we find additional examples of riboswitch-regulated homologues, suggesting that they are a frequent occurrence in bacteria. Therefore, our aggregate data discover a new and perhaps broadly important path for magnesium import and highlight how identification of riboswitch RNAs can help shed light on new, and sometimes unexpected, functions of their downstream genes. ; Magnesium ions are essential for life, and, correspondingly, all organisms must encode for proteins to transport them. Three classes of bacterial proteins (CorA, MgtE and MgtA/B) have previously been identified for transport of the ion. This current study introduces a new route of magnesium import, which, moreover, is unexpectedly provided by proteins distantly related to Natural esistance-ssociated acrophage roteins (Nramp). Nramp metal transporters are widespread in the three domains of life; however, most are assumed to function as transporters of transition metals such as manganese or iron. None of the previously characterized Nramps have been shown to transport magnesium. In this study, we demonstrate that certain bacterial proteins, distantly related to Nramp homologues, exhibit transport of magnesium. We also find that these new magnesium transporters are genetically controlled by a magnesium-sensing regulatory element. Importantly, we find numerous additional examples of similar genes sharing this regulatory arrangement, suggesting that these genes may be a frequent occurrence in bacteria, and may represent a class of magnesium transporters. Therefore, our aggregate data discover a new and perhaps broadly important path of magnesium import in bacteria.
    Keywords: Research Article ; Biology And Life Sciences ; Research And Analysis Methods
    ISSN: 1553-7390
    E-ISSN: 1553-7404
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