Mechanisms of bacterial heme uptake and degradation: Diverse strategies for ring opening

Abstract

Iron acquisition by bacterial pathogens is critical for their survival and virulence within the host. Heme represents a viable source of iron by which pathogens overcome the limited iron availability and establish infection. Over the past decade several new paradigms in bacterial heme degradation have been identified. Herein, we will briefly discuss the mechanisms by which bacterial pathogens acquire and utilize heme with a particular focus on the three major classes of heme-degrading enzymes: the canonical heme oxygenases (HO), the non-canonical HOs, and the class C radical SAM methyl transferases. The canonical HO enzymes typified by the gram-negative pathogens Pseudomonas aeruginosa and Neisseriae meningitidis were shown to be structurally and mechanistically similar to the eukaryotic HO enzymes. In contrast, the non-canonical HOs of the gram-positive pathogen Staphylococcus aureus and Mycobacterium tuberculosis have a distinct ferredoxin-like structural fold and extreme heme ruffling that gives rise to alternate heme metabolites. Enteric pathogens such as E. coli O157:H7 and Vibrio cholera encode a heme-dependent radical SAM methyl transferase that opens the porphyrin ring in an oxygen-independent manner essential in the anoxic environment of the gut. All three classes of heme-degrading enzymes provide an advantage for survival within the host, while also yielding metabolites that play a role in bacterial adaptation and virulence. Therefore, a complete understanding of the distinct mechanisms of heme degradation and the role of the unique heme metabolites will provide a platform for the development of antibacterial strategies targeting heme catabolism.