Superoxide (O-2.(-)) and peroxynitrite (ONOO-) have been implicated in many pathophysiological conditions. To develop novel catalysts that have both ONOO- decomposition and O-2.(-) dismutase activity, and to understand the mechanisms of these processes, we have explored the reactivity of 5,10, 15,20-tetrakis(N-methyl-4'-pyridyl)porphinatomanganese [Mn(III)TMPyP] toward ONOO- and O-2.(-). The reaction of Mn(III)TMPyP with ONOO- to generate an oxomanganese(IV) porphyrin species [(oxoMn(IV)] is fast, but Mn(III)TMPyP is not catalytic for ONOO- decomposition because of the slow reduction of oxoMn(IV) back to the Mn(III) oxidation state. However, biological antioxidants such as ascorbate, glutathione, and Trolox rapidly turn over the catalytic cycle by reducing oxoMn(IV). Thus, Mn(III)TMPyP becomes an efficient peroxynitrite reductase when coupled with ascorbate, glutathione, and Trolox (k(c) approximate to 2 x 10(6) M-1 s(-1)), though the direct reactions of ONOO- with these biological antioxidants are slow (88 M-1 s(-1), 5.8 x 10(2) M-1 s(-1) and 33 M-1 s(-1), respectively). Mn(In)TMPyP is known to catalyze the dismutation of O-2.(-), and using stopped-flow spectrophotometry, the rate of Mn(III)TMPyP-catalyzed dismutation has been measured directly (k(c)= 1.1 x 10(7) M-1 s(-1)). Further, O-2.(-), like the biological antioxidants, rapidly reduces oxoMn(IV) to the Mn(III) oxidation state (k approximate to 10(8) M-1 s(-1)), transforming Mn(III)TMPyP into a O-2.(-)-coupled ONOO-reductase. Under conditions of oxidative stress and reduced antioxidant levels, Mn(III)TMPyP may deplete O-2.(-) primarily as a function of its ONOO- reductase activity, and not through its O-2.(-) dismutase activity.