On mechanism of superoxide signaling under physiological and pathophysiological conditions

It has been demonstrated that in various physiological and pathophysiological processes superoxide functions as a signaling molecule by the way different from those mediated by hydrogen peroxide, hydroxyl radicals, or peroxynitrite. However, until now the mechanism of superoxide signaling remains obscure. A well known role of superoxide as a precursor of reactive hydroxyl radicals by the superoxide-dependent Fenton reaction or the formation of peroxynitrite must result in the damage of the target molecules and lead to pathological disorders. However, this mechanism is unlikely in such processes as the stimulation by superoxide of enzymatic phosphorylation and dephosphorylation. But, not being a "super-oxidant", superoxide possesses the frequently forgotten "super"-nucleophilic properties. Now, we propose a new mechanism for superoxide signaling depending on its nucleophilic reactions. Possible nucleophilic mechanisms of superoxide signaling in the hydrolysis of phosphatidylinositol to inositol 1,4,5-tris-phosphate and in the catalysis of phosphorylation by mitogen-activated protein kinases, phospholipase C and other enzymes are considered.