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Heme constitutes the largest iron reservoir in the human body and is utilized by many bacterial pathogens as an iron source. While heme acquisition is well studied in other bacterial pathogens, little is known in\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    . To identify proteins involved in heme utilization by\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    , a transposon mutant library was screened for resistance to the toxic heme analog gallium(III)-porphyrin (Ga-PIX). Inactivation of the\n                    <jats:italic>ppe36<\/jats:italic>\n                    ,\n                    <jats:italic>ppe62<\/jats:italic>\n                    , and\n                    <jats:italic>rv0265c<\/jats:italic>\n                    genes resulted in resistance to Ga-PIX. Growth experiments using isogenic\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    deletion mutants showed that PPE36 is essential for heme utilization by\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    , while the functions of PPE62 and Rv0265c are partially redundant. None of the genes restored growth of the heterologous\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    mutants, indicating that the proteins encoded by the genes have separate functions. PPE36, PPE62, and Rv0265c bind heme as shown by surface plasmon resonance spectroscopy and are associated with membranes. Both PPE36 and PPE62 proteins are cell surface accessible, while the Rv0265c protein is probably located in the periplasm. PPE36 and PPE62 are, to our knowledge, the first proline-proline-glutamate (PPE) proteins of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    that bind small molecules and are involved in nutrient acquisition. The absence of a virulence defect of the\n                    <jats:italic>ppe36<\/jats:italic>\n                    deletion mutant indicates that the different iron acquisition pathways of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    may substitute for each other during growth and persistence in mice. The emerging model of heme utilization by\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    as derived from this study is substantially different from those of other bacteria.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Tuberculosis is caused by\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    and is a devastating disease affecting eight million people each year. Iron is an essential nutrient for replication of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    in the human host. More than 70% of iron in the human body is bound in heme. Not surprisingly, many bacterial pathogens, including\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    , are able to acquire iron from heme. However, the mechanism of heme uptake by\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    is poorly understood. We have identified two novel surface proteins that bind heme and are required for heme utilization by\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    . These findings constitute a major advancement of our understanding of iron acquisition by\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    and show that\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    has evolved heme uptake systems different from the paradigms established by other bacteria.\n                  <\/jats:p>","DOI":"10.1128\/mbio.01720-16","type":"journal-article","created":{"date-parts":[[2017,1,24]],"date-time":"2017-01-24T20:30:39Z","timestamp":1485289839000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":101,"title":["PPE Surface Proteins Are Required for Heme Utilization by\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1128","volume":"8","author":[{"given":"Avishek","family":"Mitra","sequence":"first","affiliation":[{"name":"Department of Microbiology, University of Alabama at Birmingham, Birmingham, 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