Fig. 4. Strategies to avoid heme toxicity.

Heme toxicity (center) is a combination of heme damage to membrane lipids, membrane proteins, and DNA, and oxidative damage. Oxidative damage is mediated by the production of superoxide dismutase ( ${\mathrm{O}}_2^{-}•$), hydroxyl radical (HO•), and hydroperoxyl radical (HOO•). To reduce heme damage, many Gram-positive organisms (the S. aureus system is diagrammed here) encode the HrtAB efflux pump. The HssRS two-component system responds to excess heme and activates the transcription of the hrtAB system, thus preventing the accumulation of toxic levels of heme. Alternatively, Gram-negative organisms rely on intracellular heme sequestration proteins (PhuS of P. aeruginosa, HemS of Yersinia), the periplasmic heme-binding, copper and zinc dependent superoxide dismutase (Cu,Zn SOD, of H. ducreyi), and systems that respond to hydrophobic molecules, including heme (MtrCDE efflux and Ght of Neisseria).