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: 9.81). 03/2011; 108(12):5051-6. DOI: 10.1073/pnas.1009516108
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tuberculosis threatens human health nowhere more than in developing countries with large malnourished and/or immune-compromised (e.g. HIV infected) populations. The etiological agent, Mycobacterium tuberculosis (Mtb), is highly infectious and current interventions demonstrate limited ability to control the epidemic in particular of drug resistant Mtb strains. New drugs and vaccines are thus urgently required. Structural biologists are critical to the TB research community. By identifying potential drug targets and solving their three dimensional structures they open new avenues of identifying potential inhibitors complementing the screening of novel compounds and the investigation of Mtb's molecular physiology by pharmaceutical companies and academic researchers. Much effort has gone into structurally elucidating the Mtb proteome though much remains to be done with progress primarily limited by technological constraints. We review the currently available data for Mtb H37Rv to extract the lessons they have taught us. Copyright © 2015. Published by Elsevier Ltd.
    Tuberculosis (Edinburgh, Scotland) 12/2014; 95(2). DOI:10.1016/ · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistant mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism, however, we find that instead of inhibiting uptake of iron PZP acts as an iron chelator and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 03/2015; 59(4):AAC.05114-14. DOI:10.1128/AAC.05114-14 · 4.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Iron is an essential element to most life forms including mycobacterial species. However, in the oxidative atmosphere iron exists as insoluble salts. Free and soluble iron ions are scarce in both the extracellular and intracellular environment which makes iron assimilation very challenging to mycobacteria. Tuberculosis, caused by the pathogen, Mycobacterium tuberculosis, is one of the most infectious and deadly diseases in the world. Extensive studies regarding iron acquisition strategies have been documented in mycobacteria, including work on the mycobacterial iron chelators (siderophores), the iron-responsive regulon, and iron transport and utilization pathways. Under low iron conditions, expression of the genes encoding iron importers, exporters and siderophore biosynthetic enzymes is up-regulated significantly increasing the ability of the bacteria to acquire limited host iron. Disabling these proteins impairs the growth of mycobacteria under low iron conditions both in vitro and in vivo, and that of pathogenic mycobacteria in animal models. Drugs targeting siderophore-mediated iron transport could offer promising therapeutic options. However, the discovery and characterization of an alternative iron acquisition mechanism, the heme transport and utilization pathway, questions the effectiveness of the siderophore-centered therapeutic strategy. Links have been found between these two distinct iron acquisition mechanisms, thus, targeting a few candidate proteins or mechanisms may influence both pathways, leading to effective elimination of the bacteria in the host. Copyright © 2015. Published by Elsevier Ltd.
    Tuberculosis (Edinburgh, Scotland) 01/2015; 95(2). DOI:10.1016/ · 3.50 Impact Factor

Christine Crosby