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Human mAbs to Staphylococcus aureus IsdA Provide Protection Through Both Heme-Blocking and Fc-Mediated Mechanisms.
Bennett MR, Bombardi RG, Kose N, Parrish EH, Nagel MB, Petit RA, Read TD, Schey KL, Thomsen IP, Skaar EP, Crowe JE
(2019) J Infect Dis 219: 1264-1273
MeSH Terms: Animals, Antibodies, Monoclonal, Antigens, Bacterial, Bacterial Proteins, Disease Models, Animal, Female, Hemeproteins, Humans, Hydrogen Deuterium Exchange-Mass Spectrometry, Mice, Mice, Inbred BALB C, Receptors, Cell Surface, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added March 31, 2019
The nutrient metal iron plays a key role in the survival of microorganisms. The iron-regulated surface determinant (Isd) system scavenges heme-iron from the human host, enabling acquisition of iron in iron-deplete conditions in Staphylococcus aureus during infection. The cell surface receptors IsdB and IsdH bind hemoproteins and transfer heme to IsdA, the final surface protein before heme-iron is transported through the peptidoglycan. To define the human B-cell response to IsdA, we isolated human monoclonal antibodies (mAbs) specific to the surface Isd proteins and determined their mechanism of action. We describe the first isolation of fully human IsdA and IsdH mAbs, as well as cross-reactive Isd mAbs. Two of the identified IsdA mAbs worked in a murine septic model of infection to reduce bacterial burden during staphylococcal infection. Their protection was a result of both heme-blocking and Fc-mediated effector functions, underscoring the importance of targeting S. aureus using diverse mechanisms.
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
0 Communities
3 Members
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14 MeSH Terms
Dynamic Evolution of Nitric Oxide Detoxifying Flavohemoglobins, a Family of Single-Protein Metabolic Modules in Bacteria and Eukaryotes.
Wisecaver JH, Alexander WG, King SB, Hittinger CT, Rokas A
(2016) Mol Biol Evol 33: 1979-87
MeSH Terms: Adaptation, Biological, Amino Acid Sequence, Bacteria, Bacterial Proteins, Biological Evolution, Computational Biology, Databases, Nucleic Acid, Dihydropteridine Reductase, Escherichia coli Proteins, Eukaryota, Evolution, Molecular, Fungi, Gene Duplication, Gene Transfer, Horizontal, Hemeproteins, NADH, NADPH Oxidoreductases, Nitric Oxide, Phylogeny
Show Abstract · Added April 6, 2017
Due to their functional independence, proteins that comprise standalone metabolic units, which we name single-protein metabolic modules, may be particularly prone to gene duplication (GD) and horizontal gene transfer (HGT). Flavohemoglobins (flavoHbs) are prime examples of single-protein metabolic modules, detoxifying nitric oxide (NO), a ubiquitous toxin whose antimicrobial properties many life forms exploit, to nitrate, a common source of nitrogen for organisms. FlavoHbs appear widespread in bacteria and have been identified in a handful of microbial eukaryotes, but how the distribution of this ecologically and biomedically important protein family evolved remains unknown. Reconstruction of the evolutionary history of 3,318 flavoHb protein sequences covering the family's known diversity showed evidence of recurrent HGT at multiple evolutionary scales including intrabacterial HGT, as well as HGT from bacteria to eukaryotes. One of the most striking examples of HGT is the acquisition of a flavoHb by the dandruff- and eczema-causing fungus Malassezia from Corynebacterium Actinobacteria, a transfer that growth experiments show is capable of mediating NO resistance in fungi. Other flavoHbs arose via GD; for example, many filamentous fungi possess two flavoHbs that are differentially targeted to the cytosol and mitochondria, likely conferring protection against external and internal sources of NO, respectively. Because single-protein metabolic modules such as flavoHb function independently, readily undergo GD and HGT, and are frequently involved in organismal defense and competition, we suggest that they represent "plug-and-play" proteins for ecological arms races.
© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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1 Members
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18 MeSH Terms
Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host.
Hammer ND, Reniere ML, Cassat JE, Zhang Y, Hirsch AO, Indriati Hood M, Skaar EP
(2013) mBio 4:
MeSH Terms: Aerobiosis, Animal Structures, Animals, Bacterial Proteins, Disease Models, Animal, Electron Transport Chain Complex Proteins, Female, Heme-Binding Proteins, Hemeproteins, Mice, Mice, Inbred BALB C, Oxidoreductases, Staphylococcal Infections, Staphylococcus aureus, Virulence, Virulence Factors
Show Abstract · Added May 31, 2014
UNLABELLED - Staphylococcus aureus is a significant cause of infections worldwide and is able to utilize aerobic respiration, anaerobic respiration, or fermentation as the means by which it generates the energy needed for proliferation. Aerobic respiration is supported by heme-dependent terminal oxidases that catalyze the final step of aerobic respiration, the reduction of O2 to H2O. An inability to respire forces bacteria to generate energy via fermentation, resulting in reduced growth. Elucidating the roles of these energy-generating pathways during colonization of the host could uncover attractive therapeutic targets. Consistent with this idea, we report that inhibiting aerobic respiration by inactivating heme biosynthesis significantly impairs the ability of S. aureus to colonize the host. Two heme-dependent terminal oxidases support aerobic respiration of S. aureus, implying that the staphylococcal respiratory chain is branched. Systemic infection with S. aureus mutants limited to a single terminal oxidase results in an organ-specific colonization defect, resulting in reduced bacterial burdens in either the liver or the heart. Finally, inhibition of aerobic respiration can be achieved by exposing S. aureus to noniron heme analogues. These data provide evidence that aerobic respiration plays a major role in S. aureus colonization of the host and that this energy-generating process is a viable therapeutic target.
IMPORTANCE - Staphylococcus aureus poses a significant threat to public health as antibiotic-resistant isolates of this pathogen continue to emerge. Our understanding of the energy-generating processes that allow S. aureus to proliferate within the host is incomplete. Host-derived heme is the preferred source of nutrient iron during infection; however, S. aureus can synthesize heme de novo and use it to facilitate aerobic respiration. We demonstrate that S. aureus heme biosynthesis powers a branched aerobic respiratory chain composed of two terminal oxidases. The importance of having two terminal oxidases is demonstrated by the finding that each plays an essential role in colonizing distinct organs during systemic infection. Additionally, this process can be targeted by small-molecule heme analogues called noniron protoporphyrins. This study serves to demonstrate that heme biosynthesis supports two terminal oxidases that are required for aerobic respiration and are also essential for S. aureus pathogenesis.
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2 Members
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16 MeSH Terms
Cytochrome P450-type hydroxylation and epoxidation in a tyrosine-liganded hemoprotein, catalase-related allene oxide synthase.
Boeglin WE, Brash AR
(2012) J Biol Chem 287: 24139-47
MeSH Terms: Catalase, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Gas Chromatography-Mass Spectrometry, Hemeproteins, Hydroxylation, Intramolecular Oxidoreductases, Iodobenzenes, Linoleic Acids, Magnetic Resonance Spectroscopy
Show Abstract · Added January 21, 2015
The ability of hemoproteins to catalyze epoxidation or hydroxylation reactions is usually associated with a cysteine as the proximal ligand to the heme, as in cytochrome P450 or nitric oxide synthase. Catalase-related allene oxide synthase (cAOS) from the coral Plexaura homomalla, like catalase itself, has tyrosine as the proximal heme ligand. Its natural reaction is to convert 8R-hydroperoxy-eicosatetraenoic acid (8R-HPETE) to an allene epoxide, a reaction activated by the ferric heme, forming product via the Fe(IV)-OH intermediate, Compound II. Here we oxidized cAOS to Compound I (Fe(V)=O) using the oxygen donor iodosylbenzene and investigated the catalytic competence of the enzyme. 8R-hydroxyeicosatetraenoic acid (8R-HETE), the hydroxy analog of the natural substrate, normally unreactive with cAOS, was thereby epoxidized stereospecifically on the 9,10 double bond to form 8R-hydroxy-9R,10R-trans-epoxy-eicosa-5Z,11Z,14Z-trienoic acid as the predominant product; the turnover was 1/s using 100 μm iodosylbenzene. The enantiomer, 8S-HETE, was epoxidized stereospecifically, although with less regiospecificity, and was hydroxylated on the 13- and 16-carbons. Arachidonic acid was converted to two major products, 8R-HETE and 8R,9S-eicosatrienoic acid (8R,9S-EET), plus other chiral monoepoxides and bis-allylic 10S-HETE. Linoleic acid was epoxidized, whereas stearic acid was not metabolized. We conclude that when cAOS is charged with an oxygen donor, it can act as a stereospecific monooxygenase. Our results indicate that in the tyrosine-liganded cAOS, a catalase-related hemoprotein in which a polyunsaturated fatty acid can enter the active site, the enzyme has the potential to mimic the activities of typical P450 epoxygenases and some capabilities of P450 hydroxylases.
0 Communities
1 Members
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10 MeSH Terms
The flexible loop of Staphylococcus aureus IsdG is required for its degradation in the absence of heme.
Reniere ML, Haley KP, Skaar EP
(2011) Biochemistry 50: 6730-7
MeSH Terms: Bacterial Proteins, Binding Sites, Gene Targeting, Heme, Hemeproteins, Humans, Iron, Mixed Function Oxygenases, Mutant Chimeric Proteins, Oxygenases, Point Mutation, Protein Conformation, Protein Denaturation, Protein Stability, Staphylococcus aureus
Show Abstract · Added February 11, 2016
Degradation of specific native proteins allows bacteria to rapidly adapt to changing environments when the activity of those proteins is no longer required. Although these processes are vital to bacterial survival, relatively little is known regarding how bacterial proteins are recognized and targeted for degradation. Staphylococcus aureus is an important human pathogen that requires iron for growth and pathogenesis. In the vertebrate host, S. aureus fulfills its iron requirement by obtaining heme iron from host hemoproteins via IsdG- and IsdI-mediated heme degradation. IsdG and IsdI are structurally and mechanistically analogous but are differentially regulated by iron and heme availability. Specifically, IsdG is targeted for degradation in the absence of heme. Therefore, we utilized the differential regulation of IsdG and IsdI to investigate the mechanism of regulated proteolysis. In contrast to canonical protease recognition sequences, we show that IsdG is targeted for degradation by internally coded sequences. Specifically, a flexible loop near the heme-binding pocket is required for IsdG degradation in the absence of heme.
© 2011 American Chemical Society
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1 Members
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15 MeSH Terms
Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure.
Boutaud O, Moore KP, Reeder BJ, Harry D, Howie AJ, Wang S, Carney CK, Masterson TS, Amin T, Wright DW, Wilson MT, Oates JA, Roberts LJ
(2010) Proc Natl Acad Sci U S A 107: 2699-704
MeSH Terms: Acetaminophen, Animals, Arachidonic Acids, Catalysis, Dose-Response Relationship, Drug, Hemeproteins, Hemoglobins, Humans, Hydrogen Peroxide, Hydrogen-Ion Concentration, Iron, Lipid Peroxidation, Male, Myoglobin, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Renal Insufficiency, Rhabdomyolysis, Spectrophotometry
Show Abstract · Added March 7, 2014
Hemoproteins, hemoglobin and myoglobin, once released from cells can cause severe oxidative damage as a consequence of heme redox cycling between ferric and ferryl states that generates radical species that induce lipid peroxidation. We demonstrate in vitro that acetaminophen inhibits hemoprotein-induced lipid peroxidation by reducing ferryl heme to its ferric state and quenching globin radicals. Severe muscle injury (rhabdomyolysis) is accompanied by the release of myoglobin that becomes deposited in the kidney, causing renal injury. We previously showed in a rat model of rhabdomyolysis that redox cycling between ferric and ferryl myoglobin yields radical species that cause severe oxidative damage to the kidney. In this model, acetaminophen at therapeutic plasma concentrations significantly decreased oxidant injury in the kidney, improved renal function, and reduced renal damage. These findings also provide a hypothesis for potential therapeutic applications for acetaminophen in diseases involving hemoprotein-mediated oxidative injury.
1 Communities
3 Members
0 Resources
20 MeSH Terms
Enzymatic synthesis of a bicyclobutane fatty acid by a hemoprotein lipoxygenase fusion protein from the cyanobacterium Anabaena PCC 7120.
Schneider C, Niisuke K, Boeglin WE, Voehler M, Stec DF, Porter NA, Brash AR
(2007) Proc Natl Acad Sci U S A 104: 18941-5
MeSH Terms: Anabaena, Bacterial Proteins, Catalase, Chromatography, High Pressure Liquid, Conserved Sequence, Epoxy Compounds, Hemeproteins, Hexanes, Leukotriene A4, Linoleic Acids, Linolenic Acids, Lipoxygenase, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Oleic Acids, Peptide Fragments, Peroxidases, Protein Structure, Tertiary, Recombinant Proteins, Sequence Homology, Amino Acid, Spectrophotometry, Ultraviolet
Show Abstract · Added December 10, 2013
Biological transformations of polyunsaturated fatty acids often lead to chemically unstable products, such as the prostaglandin endoperoxides and leukotriene A(4) epoxide of mammalian biology and the allene epoxides of plants. Here, we report on the enzymatic production of a fatty acid containing a highly strained bicyclic four-carbon ring, a moiety known previously only as a model compound for mechanistic studies in chemistry. Starting from linolenic acid (C18.3omega3), a dual function protein from the cyanobacterium Anabaena PCC 7120 forms 9R-hydroperoxy-C18.3omega3 in a lipoxygenase domain, then a catalase-related domain converts the 9R-hydroperoxide to two unstable allylic epoxides. We isolated and identified the major product as 9R,10R-epoxy-11trans-C18.1 containing a bicyclo[1.1.0]butyl ring on carbons 13-16, and the minor product as 9R,10R-epoxy-11trans,13trans,15cis-C18.omega3, an epoxide of the leukotriene A type. Synthesis of both epoxides can be understood by initial transformation of the hydroperoxide to an epoxy allylic carbocation. Rearrangement to an intermediate bicyclobutonium ion followed by deprotonation gives the bicyclobutane fatty acid. This enzymatic reaction has no parallel in aqueous or organic solvent, where ring-opened cyclopropanes, cyclobutanes, and homoallyl products are formed. Given the capability shown here for enzymatic formation of the highly strained and unstable bicyclobutane, our findings suggest that other transformations involving carbocation rearrangement, in both chemistry and biology, should be examined for the production of the high energy bicyclobutanes.
0 Communities
4 Members
0 Resources
21 MeSH Terms
Unusual susceptibility of heme proteins to damage by glucose during non-enzymatic glycation.
Cussimanio BL, Booth AA, Todd P, Hudson BG, Khalifah RG
(2003) Biophys Chem 105: 743-55
MeSH Terms: Animals, Cattle, Free Radicals, Glucose, Glycation End Products, Advanced, Glycosylation, Hemeproteins, Hemoglobins, Horses, Humans, Hydrogen Peroxide, Iron, Myoglobin, Oxidation-Reduction, Spectrum Analysis
Show Abstract · Added December 10, 2013
Glucose modifies the amino groups of proteins by a process of non-enzymatic glycation, leading to potentially deleterious effects on structure and function that have been implicated in the pathogenesis of diabetic complications. These changes are extremely complex and occur very slowly. We demonstrate here that hemoglobin and myoglobin are extremely susceptible to damage by glucose in vitro through a process that leads to complete destruction of the essential heme group. This process appears in addition to the expected formation of so-called advanced glycation end products (AGEs) on lysine and other side-chains. AGE formation is enhanced by the iron released. In contrast, the heme group is not destroyed during glycation of cytochrome c, where the sixth coordination position of the heme iron is not accessible to solvent ligands. Glycation leads to reduction of ferricytochrome c in this case. Since hydrogen peroxide is known to destroy heme, and the destruction observed during glycation of hemoglobin and myoglobin is sensitive to catalase, we propose that the degradation process is initiated by hydrogen peroxide formation. Damage may then occur through reaction with superoxide generated (a reductant of ferricytochrome c), or hydroxyl radicals, or with both.
1 Communities
1 Members
0 Resources
15 MeSH Terms
Rate-limiting steps in cytochrome P450 catalysis.
Guengerich FP
(2002) Biol Chem 383: 1553-64
MeSH Terms: Catalysis, Computer Simulation, Cytochrome P-450 Enzyme System, Dealkylation, Ferrous Compounds, Hemeproteins, Humans, Kinetics, Oxidation-Reduction, Thermodynamics
Show Abstract · Added May 26, 2014
Cytochrome P450 (P450) reactions are of interest because of their relevance to the oxidative metabolism of drugs, steroids, carcinogens, and other chemicals. One of the considerations about functional characterization is which steps of the catalytic cycle are rate-limiting. Detailed analysis indicates that several different steps can be rate-limiting with individual P450 reactions. N-Dealkylation of para-substituted N,N-dimethylanilines is a function of the electron withdrawing/donating properties of the substituent and the oxidation-reduction potential of the substrate, supporting a role in rate-limiting electron transfer from substrate to the high valent P450. In the oxidations of ethanol and acetaldehyde by human P450 2E1, a step following product formation must be the slow step (but not product release per se). Several oxidations catalyzed by human P450s 1A2 and 2D6 show slow C-H bond breaking, and apparent high-valent iron complexes accumulate in the reaction steady-state. Kinetic simulations were used to test the suitability of potential schemes and to probe the effects of changes in individual reaction steps.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Rational design of a functional metalloenzyme: introduction of a site for manganese binding and oxidation into a heme peroxidase.
Wilcox SK, Putnam CD, Sastry M, Blankenship J, Chazin WJ, McRee DE, Goodin DB
(1998) Biochemistry 37: 16853-62
MeSH Terms: Binding Sites, Cytochrome-c Peroxidase, Hemeproteins, Manganese, Metalloproteins, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Oxidation-Reduction, Peroxidases, Protein Conformation, Protein Engineering, Substrate Specificity
Show Abstract · Added December 10, 2013
The design of a series of functionally active models for manganese peroxidase (MnP) is described. Artificial metal binding sites were created near the heme of cytochrome c peroxidase (CCP) such that one of the heme propionates could serve as a metal ligand. At least two of these designs, MP6.1 and MP6.8, bind Mn2+ with Kd congruent with 0.2 mM, react with H2O2 to form stable ferryl heme species, and catalyze the steady-state oxidation of Mn2+ at enhanced rates relative to WT CCP. The kinetic parameters for this activity vary considerably in the presence of various dicarboxylic acid chelators, suggesting that the similar features displayed by native MnP are largely intrinsic to the manganese oxidation reaction rather than due to a specific interaction between the chelator and enzyme. Analysis of pre-steady-state data shows that electron transfer from Mn2+ to both the Trp-191 radical and the ferryl heme center of compound ES is enhanced by the metal site mutations, with transfer to the ferryl center showing the greatest stimulation. These properties are perplexingly similar to those reported for an alternate model for this site (1), despite rather distinct features of the two designs. Finally, we have determined the crystal structure at 1.9 A of one of our designs, MP6.8, in the presence of MnSO4. A weakly occupied metal at the designed site appears to coordinate two of the proposed ligands, Asp-45 and the heme 7-propionate. Paramagnetic nuclear magnetic resonance spectra also suggest that Mn2+ is interacting with the heme 7-propionate in MP6.8. The structure provides a basis for understanding the similar results of Yeung et al. (1), and suggests improvements for future designs.
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12 MeSH Terms