Biological Production, Detection, and Fate of Hydrogen Peroxide

Significance: Hydrogen peroxide (H2O2) is generated in numerous biological processes. It transmits cellular signals, contributes to oxidative folding of exported proteins, and, in excess, can be damaging to cells and tissues. Although a strong oxidant, high activation energy barriers make it unreactive with most biological molecules. Its main reactions are with transition metal centers, selenoproteins and selected thiol proteins, with glutathione peroxidases (GPxs) and peroxiredoxins (Prxs) being major targets. It reacts slowly with most thiol proteins, and how they become oxidized during redox signal transmission is not well understood. Recent Advances: Kinetic analysis indicates that Prxs and GPxs are overwhelmingly favored as targets for H2O2 in cells. Studies with localized probes indicate that H2O2 can be produced in cellular microdomains and be consumed by highly reactive targets before it can diffuse to other parts of the cell. Inactivation of these targets alone will not confine it to its site of production. Kinetic data indicate that oxidation of regulatory thiol proteins by H2O2 requires a facilitated mechanism such as directed transfer from source to target or a relay mediated through a highly reactive sensor. Critical Issues and Future Directions: Absolute rates of H2O2 production and steady-state concentrations in cells still need to be characterized. More information on cellular sites of production and action is required, and specific mechanisms of oxidation of regulatory proteins during redox signaling require further characterization.