Human neuronal nitric oxide synthase can catalyze one-electron reduction of adriamycin: role of flavin domain |
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Authors: | Fu Jie Yamamoto Keita Guan Zhi-Wen Kimura Shigenobu Iyanagi Takashi |
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Affiliation: | Department of Life Science, Graduate School of Science, Himeji Institute of Technology, Harima Science Garden City, Hyogo 678-1297, Japan. |
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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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Keywords: | Human neuronal nitric oxide synthase One-electron reduction of quinones Adriamycin Flavin semiquinone NADPH-cytochrome P450 reductase |
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