Abstract
Copper,zinc superoxide dismutase (Cu,Zn-SOD) catalyzes the HCO(3)(-)-dependent oxidation of diverse substrates. The mechanism of these oxidations involves the generation of a strong oxidant, derived from H(2)O(2), at the active site copper. This bound oxidant then oxidizes HCO(3)(-) to a strong and diffusible oxidant, presumably the carbonate anion radical that leaves the active site and then oxidizes the diverse substrates. Cu,Zn-SOD is also subject to inactivation by H(2)O(2). It is now demonstrated that the rates of HCO(3)(-)-dependent oxidations of NADPH and urate exceed the rate of inactivation of the enzyme by approximately 100-fold. Cu,Zn-SOD is also seen to catalyze a HCO(3)(-)-dependent consumption of the H(2)O(2) and that HCO(3)(-) does not protect Cu,Zn-SOD against inactivation by H(2)O(2). A scheme of reactions is offered in explanation of these observations.
Highlights
The inactivation of Cu,Zn-SOD by H2O2 and its ability to act as a nonspecific peroxidase were described (1, 9) long before the dependence of the latter activity on HCO3Ϫ was appreciated (2–5)
HCO3Ϫ-dependent Oxidation of NADPH and Urate—Were the processes presented by Reactions a– h correct we would expect the bound oxidant produced by Reaction b to inactivate the enzyme by Reaction d or, in the oxidize extraneous substrates through pthreesemnecdeiaotfioHnCoOf 3ϪC,Ot3.o
Because HCO3Ϫ does not much change the rate of inactivation of Cu,Zn-SOD by H2O2 and did not affect the rate of reduction of this enzyme by H2O2 (4), it cannot be the case that HCO3Ϫ increases the binding of H2O2 as has been suggested (2)
Summary
The rate constant for reaction leading to the formation of the copper-bound oxidant was estimated to be only 0.1 MϪ1 sϪ1 at pH 7.4 (12), which is not fast enough to account for the rapid HCO3Ϫ-dependent oxidations (2, 4). The mechanism of the interaction of H2O2 with the Cu,Zn-SOD and the effects of HCO3Ϫ require further clarifica-. In this scheme SH2 denotes a substrate such as NADPH, and His denotes a histidine residue in the ligand field of the copper. We consider the oxidant to be bound rather than diffusible because HO1⁄7 scavengers, such as ethanol, do not protect (1) and because the oxidation of large substrates depends upon the mediation of bicarbonate (2–5).
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