We suggest that the metabolism of pyruvate via the PoxB

route compensates for reduced activities of Fe-S cluster enzymes in the TCA cycle. The pathway catalyzed by PoxB is iron-independent. The E. coli ortholog, a thiamin/flavin-dependent enzyme activated by binding to IM phospholipids, Dabrafenib ic50 was shown to feed electrons directly from the cytosol to the respiratory chain [52]. To our knowledge, this is the first report linking enhanced PoxB activities in bacteria specifically to iron starvation. PoxB is a potential drug target in the context of intracellular pathogens surviving in environments where iron is sequestered. Conclusions Proteomic surveys of Y. pestis subcellular fractions grown under iron-replete vs. iron-starved conditions supported the physiological importance of the iron acquisition systems Ybt, Yfe, Yfu, Yiu and Hmu. An uncharacterized TonB-dependent OM receptor, Y0850, was also highly abundant in iron-depleted cells, appeared to be Fur-regulated and may participate in iron uptake. Numerous enzymes harboring iron and Fe-S cluster cofactors were significantly

decreased in abundance in iron-starved cells, suggesting a regulatory process shifting the metabolism of Y. pestis to iron-independent Z-VAD-FMK concentration pathways when the supply of this metal ion is limited. Small Fur-regulated RNAs termed RyhB in E. coli may be involved in this process. Finally, this study revealed biochemical pathways likely essential for the iron starvation response in Y. pestis. Examples are the energy metabolism via the pyruvate oxidase route and Fe-S cluster assembly mediated by the Suf system. Acknowledgements This work was performed under the Pathogen Functional Genomics Resource Center contract (contract No. N01-AI15447), funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Jasmine Pollard for the graphic presented in Figure 4, Christine Bunai for the development of the mass spectrometry analysis platform

and John Braisted for advice on statistical data analysis methods. Electronic supplementary material Additional file 1: Yersinia pestis growth curves in PMH2 medium. Growth curves (OD600) are displayed in graphical form for Y. pestis KIM6+ cell cultures in iron rich and iron-depleted media, at 26°C and at 37°C. (DOC 133 KB) Additional file 2: Comprehensive list of differentially displayed Yersinia pestis proteins comparing iron-replete and iron starvation Nintedanib (BIBF 1120) conditions. A variety of qualitative and quantitative data are provided for differentially displayed proteins derived from + Fe vs. -Fe growth conditions, from cell cultures at 26°C and at 37°C. (XLS 130 KB) Additional file 3: Comprehensive list of MS and MS 2 data for Y. pestis KIM6+ proteins. For all proteins listed in the Tables 1, 2 and 3 and in the Additional File 2, MS and MS2 data were parsed from MALDI-TOFTOF and LC-nESI-LC-MS/MS datasets. (XLS 6 MB) References 1. Brubaker RR, Sussman M: Yersinia pestis. In Molecular Medical Microbiology. Volume 3.