Intracellular metalloporphyrin metabolism in Staphylococcus aureus

Abstract

The bacterial pathogen Staphylococcus aureus is responsible for a significant amount of human morbidity and mortality, and the ability of S. aureus to cause disease is absolutely dependent on the acquisition of iron from the host. The most abundant iron source to invading staphylococci is in the form of the porphyrin heme. S. aureus is capable of acquiring nutrient iron from heme and hemoproteins via two heme-acquisition systems, the iron-regulated surface determinant system (Isd) and the heme transport system (Hts). Heme acquisition through these systems is involved in staphylococcal pathogenesis suggesting that the intracellular fate of heme plays a significant role in the infectious process. The valuable heme molecule presents a paradox to invading bacteria because although heme is an abundant source of nutrient iron, the extreme reactivity of heme makes it toxic at high concentrations. Therefore, bacteria must regulate the levels of intracellular heme to avoid toxicity. Although the molecular mechanisms responsible for staphylococcal heme acquisition are beginning to emerge, the mechanisms by which S. aureus regulate intracellular heme homeostasis are largely unknown. In this review we describe three potential fates of host-derived heme acquired by S. aureus during infection: (i) degradation for use as a nutrient iron source, (ii) incorporation into bacterial heme-binding proteins for use as an enzyme cofactor, or (iii) efflux through a dedicated ABC-type transport system. We hypothesize that the ultimate fate of exogenously acquired heme in S. aureus is dependent upon the intracellular and extracellular availability of both iron and heme.

Direct Hemin Transfer from IsdA to IsdC in the Iron-regulated Surface Determinant (Isd) Heme Acquisition System of Staphylococcus aureus

“…It has previously been hypothesized that hemin is transferred in the following order: IsdH-haptoglobin-hemoglobin/IsdBhemoglobin 3 IsdA 3 IsdC 3 IsdDEF and/or HtsABC (25,26). Rapid and direct hemin transfer from IsdA to IsdC provides the first piece of experimental evidence supporting this hypothesis.…”

“…IsdB, IsdA, and IsdC bind heme (11,19,20,23,24), and structural studies show that IsdA and IsdC bind hemin in a pentacoordinate complex with a tyrosine residue as the only axial ligand (19,20), in contrast to the hexacoordination of the heme iron in Shp and HtsA (14,15). It has been proposed that IsdH and IsdB capture haptoglobin-hemoglobin and hemoglobin, respectively, and heme is transferred from bound hemoglobin to IsdA, then IsdC, and finally to ABC transporters IsdDEF and/or HtsABC (25,26). This hypothesis has not been experimentally tested, and little is known about the biochemical mechanism of heme acquisition by this system.…”

Bacteria capture iron from heme by keeping tetrapyrrol skeleton intact

“…They involve extracellular hemoproteins (hemophores) that capture heme and deliver it to bacteria (2, 3) and cell surface receptors that bind heme, hemoproteins, and/or hemophores. Surface receptors of Gram-positive bacteria are cell-wallanchored proteins that scavenge heme and relay it to specific ABC transporters involved in heme internalization (4).…”

Is the host heme incorporated in microbial heme‐proteins?

“…However, the analysis of more than 70 complete bacterial genomes identified an unexpectedly small number of bacterial HO orthologs, strongly suggesting that heme degradation could also involve enzymes that do not share significant homology with eukaryotic HOs (9). Recently, a new family of monooxygenases that degrade heme by a pathway differing from canonical HOs has been reported in some pathogenic gram-positive bacteria, including Staphyloccoccus aureus, Listeria monocytogenes, and Bacillus anthracis (10). Although more enzymes implicated in heme degradation are likely be discovered in the future, the paucity of identifiable heme-degrading enzymes in bacteria that utilize extracellular heme raises the possibility that heme degradation is only one of the possible pathways of heme processing in the bacterial cytoplasm (4).…”