Repairing oxidized proteins in the bacterial envelope using respiratory chain electrons

The identification of an enzymatic system repairing proteins containing oxidized methionine in the bacterial cell envelope, a compartment particularly susceptible to oxidative damage by host defence mechanisms. Frédéric Barras and colleagues report the identification of an enzyme system, MsrPQ, which repairs a wide range of periplasmic proteins with oxidatively damaged methionine (methionine sulfoxide, Met-O) in the bacterial cell envelope, a compartment that is particularly susceptible to oxidative damage by host defence mechanisms. MsrP and MsrQ are widely distributed in Gram-negative bacteria and are expressed following exposure to hypochlorous acid, a powerful antimicrobial agent that is released by neutrophils. Interestingly, the MsrPQ repair system is functionally distinct from conventional methionine sulfoxide reductases as it exhibits non-stereospecificity and can reduce both R- and S-diastereoisomers of Met-O. Furthermore, the authors report a novel mechanism of action for MsrPQ in which electrons from the respiratory chain are used for reducing power, establishing a new link between metabolism and cellular integrity. The reactive species of oxygen and chlorine damage cellular components, potentially leading to cell death. In proteins, the sulfur-containing amino acid methionine is converted to methionine sulfoxide, which can cause a loss of biological activity. To rescue proteins with methionine sulfoxide residues, living cells express methionine sulfoxide reductases (Msrs) in most subcellular compartments, including the cytosol, mitochondria and chloroplasts1,2,3. Here we report the identification of an enzymatic system, MsrPQ, repairing proteins containing methionine sulfoxide in the bacterial cell envelope, a compartment particularly exposed to the reactive species of oxygen and chlorine generated by the host defence mechanisms. MsrP, a molybdo-enzyme, and MsrQ, a haem-binding membrane protein, are widely conserved throughout Gram-negative bacteria, including major human pathogens. MsrPQ synthesis is induced by hypochlorous acid, a powerful antimicrobial released by neutrophils. Consistently, MsrPQ is essential for the maintenance of envelope integrity under bleach stress, rescuing a wide series of structurally unrelated periplasmic proteins from methionine oxidation, including the primary periplasmic chaperone SurA. For this activity, MsrPQ uses electrons from the respiratory chain, which represents a novel mechanism to import reducing equivalents into the bacterial cell envelope. A remarkable feature of MsrPQ is its capacity to reduce both rectus (R-) and sinister (S-) diastereoisomers of methionine sulfoxide, making this oxidoreductase complex functionally different from previously identified Msrs. The discovery that a large class of bacteria contain a single, non-stereospecific enzymatic complex fully protecting methionine residues from oxidation should prompt a search for similar systems in eukaryotic subcellular oxidizing compartments, including the endoplasmic reticulum.