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)porphyr in (MnTMPyP) were evaluated for their reaction with peroxynitrite. The Mn(I II) complexes reacted with peroxynitrite anion with rate constants of 1.85 x 10(7), 3.82 x 10(6),and 4.33 x 10(6) M-1 s(-1) at 37 degrees 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 rea cted 5-fold faster than the other two isomers. The oxo-Mn(IV) complexes-cou ld in turn be reduced by glutathione, ascorbate, urate, or oxidize tyrosine . The rate constants for the reduction of the oxo-Mn(IV) complexes ranged f rom > 10(7) M-1 s(-1) for ascorbate to 10(3)-10(4) M-1 s(-1) for tyrosine a nd glutathione. Cyclic voltammetry experiments show that there is no signif icant difference in the E-1/2 Of the Mn(IV)Mn(III) couple; thus, the differ ential reactivity of the three isomeric complexes is interpreted in terms o f electrostatic and steric effects. Micromolar concentrations of MnTM-2-PyP compete well with millimolar CO2 at reacting with ONOO-, and it can even s cavenge a fraction of the ONOOCO2- that is formed. By being rapidly oxidize d by ONOO- and ONOOCO2- and reduced by antioxidants such as ascorbate, urat e, and glutathione, these manganese porphyrins, and especially MnTM-2-PyP, can redirect the oxidative potential of peroxynitrite toward natural antiox idants, thus protecting more critical targets such as proteins and nucleic acids.