Mechanisms of peroxynitrite decomposition catalyzed by FeTMPS, a bioactivesulfonated iron porphyrin

Peroxynitrite is a known cytotoxic agent that plays a role in many patholog ical conditions. Various peroxynitrite decomposition catalysts and pathways are being explored to develop efficient therapeutic agents that can safely remove peroxynitrite from cells and tissues. Water-soluble porphyrins, suc h as iron(III) meso-tetra(2,4,6-trimethyl-3,5-disulfona chloride (FeTMPS) a nd iron(III) meso-tetra(N-methyl-4-pyridyl)porphine chloride (FeTMPyP), hav e been shown to react catalytically with peroxynitrite (ONOO-). However, th eir mechanisms are yet to be fully understood. In this study, we have explo red the reactivity of FeTMPS in the catalytic decomposition of peroxynitrit e. The mechanism of this complex process has been determined. According to this mechanism, Fe(III)TMPS is oxidized by peroxynitrite to produce oxoFe(T V)TMPS and NO2 (k(1) = 1.3 x 10(5) M(-1)s(-1)). The porphyrin is then reduc ed back to Fe(III)TMPS by nitrite, but this rate (k(2) = 1.4 x 10(4) M(-1)s (-1)) is not sufficient to maintain the catalytic process at the observed r ate. The overall rate of peroxynitrite decomposition catalysis, k(cat), was determined to be 6 x 10(4) M(-1)s(-1), under typical conditions. We have p ostulated that an additional reduction pathway must exist. Kinetic simulati ons showed that a reaction of oxoFe(TV)TMPS with NO2 (k(3) = 1.7 x 10(7) M( -1)s(-1)) could explain the behavior of this system and account for the fas t reduction of oxoFe(Iv)TRIPS to Fe(III). Using the kinetic simulation anal ysis, we have also shown that two other rearrangement reactions, involving FeTMPS and peroxynitrite, are plausible pathways for peroxynitrite decay. A "cage-return" reaction between the generated oxoFe(IV)TMPS and NO2 (k(8) = 5.4 x 10(4) M-ls-l), affording Fe(III)TMPS and nitrate, and a reaction bet ween oxoFe(IV)TMPS and peroxynitrite (k(7) = 2.4 x 10(4) M(-1)s(-1)) that a ffords oxoFe(TV)TMPS and nitrate are presented. The mechanism of FeTMPS-cat alyzed peroxynitrite decay differs markedly from that of FeTMPyP, providing some insight into the reactivity of metal centers with peroxynitrite and b iologically important radicals such as NO2. (C) 2001 Academic Press.