Glutathione peroxidase hydroxide

Previously, we have examined the formation of amino acid hydroperoxides following exposure to different radical species [100]. We observed that valine was most easily oxidised, but leucine and lysine are also prone to this modification in free solution. Scheme 12 illustrates the mechanism for formation of valine hydroperoxide. However, tertiary structure becomes an important predictor in proteins, where the hydrophobic residues are protected from bulk aqueous radicals, and lysine hydroperoxides are most readily oxidised. Hydroperoxide yield is poor from Fenton-derived oxidants as they are rapidly broken down in the presence of metal ions [101]. Like methionine sulphoxide, hydroperoxides are also subject to repair, in this case via glutathione peroxidase. They can also be effectively reduced to hydroxides, a reaction supported by the addition of hydroxyl radical in the presence of oxygen. Extensive characterisation of the three isomeric forms of valine and leucine hydroxides has been undertaken by Fu et al. [102,103], and therefore will not be discussed further here. 

Allowing that the above transfer system involving Mn does occur, the cause of manganese neurotoxicity is still little understood. Archibald and Tyree [75] propose that the ability of to attack catecholamines indicates that this metal ion is toxic in itself, while other workers [76-78] see the toxicity as being due to a variety of causes such as autooxidation of dopamine, decreased glutathione (GSH) levels [64,79], reduced GSH peroxidase and brain catalase [79], and Mn -induced production either of toxic catecholamines and quinones [77] or of reactive oxo species such as superoxide, hydroxide radicals, or hydrogen peroxide [77,80,81]. A further excellent summary of much of the above detail is given by Donaldson and Barbeau [82]. 

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