Discovery and characterization of a unique mycobacterial heme acquisition system

Departments of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2011; 108(12):5051-6. DOI: 10.1073/pnas.1009516108
Source: PubMed


Mycobacterium tuberculosis must import iron from its host for survival, and its siderophore-dependent iron acquisition pathways are well established. Here we demonstrate a newly characterized pathway, whereby M. tuberculosis can use free heme and heme from hemoglobin as an iron source. Significantly, we identified the genomic region, Rv0202c-Rv0207c, responsible for the passage of heme iron across the mycobacterial membrane. Key players of this heme uptake system were characterized including a secreted protein and two transmembrane proteins, all three specific to mycobacteria. Furthermore, the crystal structure of the key heme carrier protein Rv0203 was found to have a unique fold. The discovery of a unique mycobacterial heme acquisition pathway opens new avenues of exploration into mycobacterial therapeutics.

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    • "The cytoplasmic domain C1 is positioned between the transmembrane α-helices 6 and 7 (Tullius et al., 2011; Owens et al., 2013). The extracellular domains E1 and E2 have been reported to bind haem, whereas the cytoplasmic domain C1 does not recognize the metalporphyrin (Tullius et al., 2011). In particular, the E1 domain of MmpL11 and MmpL3 binds haem with the 1:1 stoichiometry and high affinity, apparent values of K d (¼k off(Fe(III)) /k on(Fe(II)–CO) ) being 6.3 Â 10 À9 and 1.2 Â 10 À10 M for haem–Fe binding to MmpL11-E1 and MmpL3-E1, respectively. "
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    ABSTRACT: Iron plays a key role in a wide range of metabolic and signalling functions representing an essential nutrient for almost all forms of life. However, the ferric form is hardly soluble, whereas the ferrous form is highly toxic. Thus, in biological fluids, most of the iron is sequestered in iron- or haem-binding proteins and the level of free iron is low, making haem and iron acquisition a challenge for pathogenic bacteria during infections. Although toxic to the host, free haem is a major and readily available source of iron for several pathogenic microorganisms. Both Gram-positive and Gram-negative bacteria have developed several strategies to acquire free haem-Fe and protein-bound haem-Fe. Haemophores are a class of secreted and cell surface-exposed proteins promoting free-haem uptake, haem extraction from host haem proteins, and haem presentation to specific outer-membrane receptors that internalize the metal-porphyrins. Here, structural biology of bacterial haemophores is reviewed focusing on haem acquisition, haem internalization, and haem-degrading systems.
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    • " mycobacteria ( Warrier et al . , 2012 ) . Moreover , antigen 85A and 85B have been demonstrated as promising vaccine candidates for pathogenic M . tuberculosis and MAP ( Huygen et al . , 2010 ) . Many Mycobacterial membrane protein Large ( MmpL ) genes are also associated with the mycolic acid biosynthesis of cell wall ( Varela et al . , 2012 ) . Tullius et al . ( 2011 ) have demonstrated that MmpL3 in M . tuberculosis plays a pivotal role in pathogenesis and is involved in the essential iron transport across the cell wall and membrane . MAP3641c ( probable MmpL3 ) protein is therefore also an interesting antigen for further evaluation . In addition , selected MAP1239c , MAP1240c , MAP2239 and MAP3890"

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    • "Many Mycobacterial membrane protein Large (MmpL) genes are also associated with the mycolic acid biosynthesis of cell wall (Varela et al., 2012). Tullius et al. (2011) have demonstrated that MmpL3 in M. tuberculosis plays a pivotal role in pathogenesis and is involved in the essential iron transport across the cell wall and membrane. MAP3641c (probable MmpL3) protein is therefore also an interesting antigen for further evaluation. "
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    ABSTRACT: Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of paratuberculosis disease affecting ruminants worldwide. The aim of this study was to identify potential candidate antigens and epitopes by bio and immuno-informatic tools which could be later evaluated as vaccines and/or diagnosis. 110 protein sequences were selected from MAP K-10 genome database: 48 classified as putative enzymes involved in surface polysaccharide and lipopolysaccharide synthesis, as membrane associated and secreted proteins, 32as conserved membrane proteins, and 30as absent from other mycobacterial genomes. These 110 proteins were preliminary screened for Major Histocompatibility Complex (MHC) class II affinity and promiscuity using ProPred program. In addition, subcellular localization and host protein homology was analyzed. From these analyses, 23 MAP proteins were selected for a more accurate inmunoinformatic analysis (i.e. T cell and B cell epitopes analysis) and for homology with mycobacterial proteins. Finally, eleven MAP proteins were identified as potential candidates for further immunogenic evaluation: six proteins (MAP0228c, MAP1239c, MAP2232, MAP3080, MAP3131 and MAP3890) were identified as presenting potential T cell epitopes, while 5 selected proteins (MAP0232c, MAP1240c, MAP1738, MAP2239 and MAP3641c) harbored a large numbers of epitopes predicted to induce both cell- and antibody-mediated immune responses. Moreover, immunogenicity of selected epitopes from MAP1239c were evaluated in IFN-γ release assay. In summary, eleven M. avium subsp. paratuberculosis proteins were identified by in silico analysis and need to be further evaluated for their immunodiagnostic and vaccine potential in field and mice model. Copyright © 2015. Published by Elsevier Ltd.
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