The product and process of heme degradation in Staphylococcus aureus

Abstract

Staphylococcus aureus is an important human pathogen and its ability to cause disease is absolutely dependent on iron acquisition from the host. S. aureus obtains iron during infection from vertebrate hemoglobin via the iron-regulated surface determinant (Isd) system. The cytoplasmic components of this system, IsdG and IsdI, are paralagous heme oxygenases which degrade heme to release nutrient iron. I have found that although IsdG and IsdI share 64% amino acid sequence identity, they are differentially regulated depending on the microenvironment experienced by the bacterium. This may represent a strategy by which S. aureus fine-tunes the expression of heme oxygenase activity during infection, as bacteria lacking isdG or isdI exhibit differential virulence defects. In addition, these studies have identified a post-transcriptional regulatory mechanism in which IsdG is specifically stabilized in the presence of the substrate heme. Finally, we have determined the structure of the IsdG- and IsdI-catalyzed heme degradation products and shown that this family of heme oxygenases degrades heme to a novel chromophore which we have named staphylobilin. My studies have significantly advanced our understanding of heme catabolism in S. aureus, a process that I have shown is required for staphylococcal pathogenesis. Moreover, the unique structure and mechanism of the IsdG-family of heme oxygenases indicates that these enzymes may be therapeutic targets.