Catalytic Scavenging of Peroxynitrite by Isomeric Mn(III) N-Methylpyridylporphyrins in the Presence of Reductants

Three isomers of manganese(III) 5,10,15,20-tetrakis(N-methylpyridyl)porphyrin (MnTMPyP) were evaluated for their reaction with peroxynitrite. The Mn(III) complexes reacted with peroxynitrite anion with rate constants of 1.85 * 10^7, 3.82 * 10^6, and 4.33 * 10^6 M^-1 s^-1 at 37 (degree)C for MnTM-2-PyP, MnTM-3-PyP, and MnTM-4-PyP, respectively, to yield the corresponding oxo-Mn(IV) complexes. Throughout the pH range from 5 to 8.5, MnTM-2-PyP reacted 5-fold faster than the other two isomers. The oxo-Mn(IV) complexes could in turn be reduced by glutathione, ascorbate, urate, or oxidize tyrosine. The rate constants for the reduction of the oxo-Mn(IV) complexes ranged from > 10^7 M^-1 s^-1 for ascorbate to 10^3-10^4 M^-1 s^-1 for tyrosine and glutathione. Cyclic voltammetry experiments show that there is no significant difference in the E1/2 of the Mn(IV)/Mn(III) couple; thus, the differential reactivity of the three isomeric complexes is interpreted in terms of electrostatic and steric effects. Micromolar concentrations of MnTM-2-PyP compete well with millimolar CO2 at reacting with ONOO- , and it can even scavenge a fraction of the ONOOCO2- that is formed. By being rapidly oxidized by ONOOand ONOOCO2- and reduced by antioxidants such as ascorbate, urate, and glutathione, these manganese porphyrins, and especially MnTM-2-PyP, can redirect the oxidative potential of peroxynitrite toward natural antioxidants, thus protecting more critical targets such as proteins and nucleic acids.