Fig. 3.

Mechanistic details of the action of membrane-associated catalase of tumor cells (A) Tight control of NO/peroxynitrite and HOCl signaling through membrane-associated catalase of tumor cells. Membrane-associated NOX1 generates extracellular superoxide anions (#1) that form H₂O₂ after dismutation (#2). H₂O₂ is decomposed by membrane-associated catalase in a two step reaction, involving compound I (CATFe^IV=O·⁺) as intermediate (#3 and #4). Thus catalase efficiently inhibits the HOCl signaling pathway as it prevents the generation of HOCl by peroxidase (#5) and subsequent HOCl/superoxide anion interaction and formation of apoptosis-inducing hydroxyl radicals (#6). The activity of arginase (#7), the concentration of its substrate arginine, the activity of NO synthase (NOS) (#8) and the activity of NO dioxygenase (NOD) (#9) determine the concentration of free NO (#10). Compound I of catalase (CATFe^IV=O·⁺) oxidates NO to ${\mathrm{NO}}_2^{-}$ (#11) and thus counteracts NO-mediated inhibition of catalase (#12), as well as peroxynitrite formation through NO/superoxide anion interaction (#13). Residual peroxynitrite is decomposed by catalase in a two step reaction that involves the formation of compound I (#14 and # 15). Catalase-mediated oxidation of NO and decomposition of peroxynitrite prevent the formation of peroxynitrous acid (ONOOH) (#16) and its subseqent decomposition into NO₂ and apoptosis-inducing hydroxyl radicals (#17). Thus catalase establishes a tight control of the NO/peroxynitrite signaling pathway. (B) Details of the interactions between NO and catalase. NOX-derived superoxide anions (#1) dismutate to H₂O₂ (#2) which reacts with native ferricatalase (CATFe^III), resulting in the formation of compound I (CATFe^IV=O·⁺). Compound I is reduced to the inactive compound II (CATFe^IV=O) by NO in a one electron transfer reaction (#4). The resultant nitrosonium ion (NO⁺) readily reacts with water (NO⁺+H₂O→2H+${\mathrm{NO}}_2^{-}$) (#5). Compound II reacts with a second molecule of NO (#6), which leads to the formation of ${\mathrm{NO}}_2^{-}$ and to the restoration of native ferricatalase. Taken together, the oxidation of NO by catalase follows the equation H₂O₂+2·NO→2H⁺+2${\mathrm{NO}}_2^{-}$. The reaction between NO and superoxide anions results in the formation of peroxynitrite (ONOO⁻) (#7)^, which reacts with ferricatalase and leads to the formation of compound I (#8). If the concentration of NO is sufficiently high, catalase can be reversibly inhibited by NO through formation of an inactive CATFe^IIINO complex (#9). Superoxide anions reactivate NO-inhibited catalase (#10), but also can cause inhibition of the enzyme (#11) either through reduction of compound I to the inactive compound II or through formation of inactive compound III (CATFe^IIIO₂·⁻).