Subsystem: Heme, hemin uptake and utilization systems in GramPositives

This subsystem's description is:

The majority of iron in human body is found intracellularly bound to hemoproteins, while transferrin comprises only 6–7.5% of the body’s iron pool accessible to bacteria. Circulating erythrocytes are the primary iron-containing cells in the body, with between 60% and 75% of the body’s iron content being bound to hemoglobin. The oxygen storage protein, myoglobin, accounts for an additional 8–10%. Other hemoproteins, along with iron-containing proteins such as iron sulfur proteins, make up a further 4–5% of iron in the human body (Skaar, Schneewind, 2004 and refs therein).

Hemoprotein utilization is best understood in Gram-Negative bacteria (see Subsystem: "Hemin transport system"). Most of these organisms use TonB-dependent outer membrane receptors that directly bind to hemoproteins, extract, and transport the heme or the iron through the receptor cavity. A few bacteria produce hemophores that remove the heme and convey it to surface receptors and/or surface or secreted proteases that can release heme from hemoglobin. Heme or iron crosses the cytoplasmic membrane by binding protein-dependent transport systems (PBT). The proteins of heme-PBT systems share homology and sequence signatures with transporters of siderophores and vitamin B12 (Bates et al., 2003).

In Gram-Positive bacteria proteins and genes involved in heme or hemoglobin utilization are only beginning to be understood and are currently under intense investigation, especially in Staphylococci, which preferentially acquire heme-iron over other physiologically relevant iron sources (Skaar et al. 2004b). The molecular machinery responsible for staphylococcal heme acquisition is encoded by two distinct systems, the iron-regulated surface determinant system (Isd), and the heme transport system (Hts) (Mazmanian et al. 2003; Skaar et al. 2004b). The Isd heme import machinery is comprised of 10 genes (Fur-regulated), encoding 4 cell wall anchored proteins (IsdABCH), a transpeptidase (SrtB), a membrane transport system (IsdDEF), and two cytoplasmic monooxygenases (IsdGI) (reviewed in Reniere et al., 2007). Heme in S. aureus can also transit into the cytoplasm through the ABC-type transport system HtsABC, which is the more dominant heme transport system in vitro, than IsdDEF (Skaar et al. 2004b). The Hts system exhibits strong identity to permease components of the HmuTUV heme transport system of Yersinia sp., Corynebacterium sp. (Drazek et al., 2000) and other species.

Hemolytic S. pyogenes could use the hemoglobin-haptoglobin complex, hemoglobin, myoglobin, heme-albumin, and catalase, but not transferrin or lactoferrin as iron source in the human body. ABC-type transporter SiaABC located within a highly conserved, iron regulated, 10-gene operon contributes to heme uptake in this organism (Bates et al., 2002). The operon’s first gene named Shr (for streptococcal hemoprotein receptor) encodes a novel bacterial protein that bound hemoglobin, myoglobin, heme-albumin, and hemoglobin-haptoglobin (but not apo-haptoglobin). In addition to SiaABC, two other pneumococcal operons piu and pia (formerly pit1 and pit2), encoding homologous ABC transporters, were identified (Brown et al., 2001; Brown et al., 2002). The piu and pia transporters are required for the transport of inorganic iron, as well as for iron capture from hemoglobin. Significant defects in hemoglobin utilization were observed only when both loci where inactivated (Bates et al., 2003). Their homologs in other organisms may or may NOT utilize heme (and have been included in this SS as merely Auxiliary roles)

Three potential fates of host-derived heme have been suggested in S. aureus: (i) degradation for use as a nutrient iron source, (ii) incorporation into bacterial heme-binding proteins for use as an enzyme cofactor, or (iii) eflux through a dedicated transport system HrtAB (Reniere et al., 2007). When intracellular Fe concentration is low, iron can be obtain through enzymatic degradation of acquired heme. Three families of Heme oxygenases have been described: HmuO-like family (prototype in C. diphtheria (Schmitt 1997b)), the ChuS-family (E. coli (Suits et al., 2005)), and the IsdG-family of monooxygenases (first described in S. aureus (Skaar et al., 2005a)). Mechanism dealing with toxicity of acquired heme are not yet understood, however HrtAB transporter has been identified as putative heme efflux pump (Reniere et al., 2007)

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