Mechanism of iron porphyrin reactions with peroxynitrite

Peroxynitrite (ONOO^-) is a major cytotoxic agent that has been implicated in a host of pathophysiological conditions; it is therefore important to develop therapeutic agents to detoxify this potent biological oxidant, and to understand the modes of action of these agents. Water-soluble iron porphyrins, such as 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinatoiron(III) [Fe(III)TMyP] and 5,10,15,20-tetrakis-(2,4,6-trimethyl-3,5-sulfonatophenyl)porphinatoiron(III) [Fe(III)TMPS], have been shown to catalyze the efficient decomposition of ONOO^- to NO₃^- and NO₂^- under physiological conditions. However, the mechanisms of ONOO^- decomposition catalyzed by these water-soluble iron porphyrins have not yet been elucidated. We have shown that there are two different pathways operating in the catalytic decomposition of ONOO^- by FeTMPyP. Fe(III)TMyP reacts rapidly with ONOO^- to produce oxoFe(IV)TMPyP and NO₂ (k ~ 5 x 10⁷ M^-1 s^-1). The oxoFe(IV) porphyrin, which persisted throughout the catalytic decomposition of ONOO^-, was shown to be relatively unreactive toward NO₂ and NO₂^-. This oxoFe(IV) porphyrin was also shown to react with ONOO^- (k = 1.8 x 10⁶ M^-1 s^-1), and it was this oxoFe(IV)-ONOO^- reaction pathway that predominated under conditions of excess ONOO^- with respect to Fe(III)TMPyP. The competition between the two pathways explains the highly nonlinear relationship observed for k(cat) with respect to ONOO^- concentration. Fe(III)-TMPyP is also known to catalyze the dismutation of the ONOO^- precursor superoxide (O^2-.), and using stopped-flow spectrophotometry, the rate of Fe(III)TMPyP-catalyzed O₂^-. dismutation has been determined to be 1.9 x 10⁷ M^-1 s^-1 by direct measurement. A detailed mechanistic understanding of how iron porphyrins function in the catalytic decomposition of both ONOO^- and O₂^-. may prove essential in the exploration of the chemistry and biology of these reactive oxygen species, and in understanding the biological activity of these metalloporphyrins.