Fig. 2.

The NO/peroxynitrite signaling pathway A. Transformed cells. Arginase controls the level of arginine (#1) which is the substrate for NO synthase (NOS) (#2). A substantial concentration of NOS-derived NO is converted into ${\mathrm{NO}}_3^{-}$ by NO dioxygenase (NOD) (#3) that is connected to the activity of cytochrome P 450 oxidoreductase (POR). The remaining NO passes the cell membrane (#4) and reacts with NOX1-derived superoxide anions (#5), resulting in the formation of peroxynitrite (ONOO⁻) (#6). Proton pumps in the cell membrane (#7) favour the protonation of peroxynitrite to peroxynitrous acid (ONOOH) (#8). Peroxynitrous acid readily decomposes into NO₂ and hydroxyl radicals (#9), which cause lipid peroxidation (LPO) (#10) and apoptosis induction through the mitochondrial pathway of apoptosis (#11). The oxidation of NO by molecular oxygen (#12) leads to the formation of the peroxynitrite radical (ONOO.), which reacts with NO to form ONOONO (#13). ONOONO decomposes into 2 NO₂ (#14). NO₂ reacts with NO to form dinitrogentrioxide (N₂O₃) (#15). NOX1 generates extracellular superoxide anions (#16) that dismutate to H₂O₂ (#17). ${\mathrm{HO}}_2^{-}$, the anion of H₂O₂ (#18) reacts with N₂O₃, resulting in the formation of peroxynitrite (#19). The reaction between peroxynitrite and CO₂ (#20, 21) leads to the formation of nitrosoperoxycarboxylate (${\mathrm{ONOOCO}}_2^{-}$) (#22). Nitrosoperoxycarboxylate decomposes into NO₂ and the carbonate radical (CO₃^.–) (#23). CO₃·⁻ reacts with H₂O₂, resulting in the formation of HCO₃⁻+HO₂· (#24), followed by the formation of superoxide anions (#25). NO₂ reacts with NO to form N₂O₃ (#26). The reaction between H₂O₂ and peroxynitrite leads to the formation of singlet oxygen (¹O₂) (#27), whereas the reaction between H₂O₂ and hydroxyl radicals (#28, 29) might impair apoptosis induction. B. Tumor cells. The concentration of extracellular NO is controlled through steps #1–#4, as discussed under A. Nox1-derived superoxide anions (#5) dismutate to form H₂O₂ (#6) that is decomposed by membrane-associated catalase (#7), involving compound I as intermediate (CATFe^IV=O·⁺). Compound I of catalase is generated through interaction of native catalase with one molecule of H₂O₂ and oxidates NO to${\mathrm{NO}}_2^{-}$ (#8). Oxidation of NO impairs the formation of ONOO⁻ (#9, #10). Residual ONOO⁻ is decomposed by catalase in a two step reaction that involves formation of compound I (#11). The oxidation of NO and the decomposition of peroxynitrite by membrane-associated catalase causes a tight control of NO/peroxynitrite signaling.