Selenocysteine robustness versus cysteine versatility: a hypothesis on the evolution of the moonlighting behaviour of peroxiredoxins.

Peroxiredoxins (Prxs) and glutathione peroxidases (Gpxs) provide the majority of peroxides reducing activity in the cytoplasm. Both are peroxidases but differences in the chemical mechanism of reduction of oxidative agents, as well as in the reactivity of the catalytically active residues, confer peculiar features on them. Ultimately, Gpx should be regarded as an efficient peroxides scavenger having a high-reactive selenocysteine (Sec) residue. Prx, by having a low pKa cysteine, is less efficient than Gpx in reduction of peroxides under physiological conditions, but the chemistry of the sulfur together with the peculiar structural arrangement of the active site, in typical Prxs, make it suitable to sense a redox environment and to switch-in-function so as to exert holdase activity under redox-stress conditions. The complex macromolecular assembly would have evolved the chaperone holdase function and the moonlighting behaviour typical of many Prxs.

Thioredoxin reductase and its inhibitors.

Thioredoxin plays a crucial role in a wide number of physiological processes, which span from reduction of nucleotides to deoxyriboucleotides to the detoxification from xenobiotics, oxidants and radicals. The redox function of Thioredoxin is critically dependent on the enzyme Thioredoxin NADPH Reductase (TrxR). In view of its indirect involvement in the above mentioned physio/pathological processes, inhibition of TrxR is an important clinical goal. As a general rule, the affinities and mechanisms of binding of TrxR inhibitors to the target enzyme are known with scarce precision and conflicting results abound in the literature. A relevant analysis of published results as well as the experimental procedures is therefore needed, also in view of the critical interest of TrxR inhibitors. We review the inhibitors of TrxR and related flavoreductases and the classical treatment of reversible, competitive, non competitive and uncompetitive inhibition with respect to TrxR, and in some cases we are able to reconcile contradictory results generated by oversimplified data analysis.