Abstract
We have analyzed the mechanism of one-electron reduction of adriamycin (Adr) using recombinant full-length human neuronal nitric-oxide synthase and its flavin domains. Both enzymes catalyzed aerobic NADPH oxidation in the presence of Adr. Calcium/calmodulin (Ca 2+/CaM) stimulated the NADPH oxidation of Adr. In the presence or absence of Ca 2+/CaM, the flavin semiquinone radical species were major intermediates observed during the oxidation of the reduced enzyme by Adr. The FAD–NADPH binding domain did not significantly catalyze the reduction of Adr. Neither the FAD semiquinone (FADH ) nor the air-stable semiquinone (FAD–FMNH ) reacted rapidly with Adr. These data indicate that the fully reduced species of FMN (FMNH 2) donates one electron to Adr, and that the rate of Adr reduction is stimulated by a rapid electron exchange between the two flavins in the presence of Ca 2+/CaM. Based on these findings, we propose a role for the FAD–FMN pair in the one-electron reduction of Adr.
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