Heme acquisition by Mycobacterium tuberculosis

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In the late 19th century, the French physician Armand Trousseau recognized that treating anemic tuberculosis patients with iron salts exacerbated the disease because iron is essential for Mycobacterium tuberculosis to grow. In healthy people almost all iron is bound to proteins to limit the replication of bacterial pathogens. Iron accessibility is further reduced by an immune response to an infection which enhances iron sequestration. Until recently the only known mechanism of iron uptake by M. tuberculosis was based on the secretion and uptake of small molecules with high binding affinity, the so-called siderophores. We previously showed that M. tuberculosis can also utilize heme as the sole iron source which accounts for approximately 70% of the total iron in the human host. Heme acquisition by M. tuberculosis requires the two heme-binding proteins PPE36 and PPE62 for uptake across the outer membrane. However, the inner membrane heme importer was unknown. The HemTUV transporter, which is utilized by gram-negative bacteria for heme uptake across the inner membrane, is absent in Mtb. Surprisingly, in this study we found that the dipeptide transporter Dpp is required by Mtb to utilize heme as an iron source (Fig. 1A). A high resolution crystal structure of DppA, the heme-binding protein associated with the Dpp transporter, revealed a heme binding pocket (Fig. 1B). Serendipitously, we discovered an alternative heme uptake pathway which is mediated by serum albumin. Human serum albumin is the most abundant blood proteins, binds heme with high affinity and enables heme uptake by Mtb independent of the PPE and Dpp proteins (Fig. 1A). It is possible that Mtb uses the albumin pathway for heme uptake when blood is available, e.g. in destroyed lung tissue with extracellular Mtb. By contrast, intracellular Mtb may utilize surface exposed PPE proteins and the Dpp transporter for heme uptake (Fig. 1C).

Heme utilization in Mtb. (A) In the absence of albumin, the inner membrane dipeptide transporter Dpp is essential for heme utilization by Mtb. Growth of wt Mtb (circles) and Δdpp (squares) in HdB minimal medium without (cyan) or with 0.5% bovine serum albumin (red) containing 10 µM hemin. (B) Crystal structure of Mtb DppA with N- and C-terminal halves of the protein color-coded in dark and light green, respectively, and residues making contact with heme. (C) PPE surface proteins and the Dpp transporter are required for heme uptake in Mtb in the absence of albumin. There is an alternate albumin-mediated heme uptake pathway independent of PPE proteins and of the Dpp transporter.

Avishek Mitra

Research Associate, University of Alabama at Birmingham