Changing paradigms in thiology from antioxidant defense toward redox regulation

The history of free radical biochemistry is briefly reviewed in respect to major trend shifts from the focus on radiation damage toward enzymology of radical production and removal and ultimately the role of radicals, hydroperoxides, and related fast reacting compounds in metabolic regulation. Selected aspects of the chemistry of radicals and hydroperoxides, the enzymology of peroxidases, and the biochemistry of adaptive responses and regulatory phenomena are compiled and discussed under the perspective of how the fragments of knowledge can be merged to biologically meaningful concepts of regulation. It is concluded that (i) not radicals but H(2)O(2), hydroperoxides, and peroxynitrite are the best candidates for oxidant signals, (ii) peroxidases of the GPx and Prx family or functionally equivalent proteins have the chance to specifically sense hydroperoxides and to transduce the oxidant signal, (iii) redox signaling proceeds via reactions known from thiol peroxidase and redoxin chemistry, (iv) proximal targets are proteins that are modified at SH groups, and (v) redoxins are documented signal transducers but also used as terminators. The importance of kinetics for forward signaling and for sensitivity modulation by competition is emphasized and ways to restore resting conditions are discussed. Research needs to validate emerging concepts are outlined.