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Biochemistry and Biophysics |
Department of Biotechnology [R. F., A. M., K-H. L., M. Y., S. H.] and Biotechnology Research Center [N. K., M. N.], The University of Tokyo, Tokyo 113-8657, Japan; Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki 300-26, Japan [H. N., A. T.]; Institute of Medicinal Molecular Design, Tokyo 113-0033, Japan [Y. K.]; Department of Biofunction, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, 808-0196, Japan [N. N.]; RIKEN, Saitama 351-0198, Japan [M. Y.]; and CREST Research Project, Japan Science and Technology Corp., Saitama 332-0012, Japan [R. F., A. M., Y. K., N. N., M. Y.]
FK228 is a histone deacetylase (HDAC) inhibitor, the molecular mechanismof inhibition of which has been unknown. Here we show that reduction of an intramolecular disulfide bond of FK228 greatly enhanced its inhibitory activity and that the disulfide bond was rapidly reduced in cells by cellular reducing activity involving glutathione. Computer modeling suggests that one of the sulfhydryl groups of the reduced form of FK228 (redFK) interacts with the active-site zinc, preventing the access of the substrate. HDAC1 and HDAC2 were more strongly inhibited by redFK than HDAC4 and HDAC6. redFK was less active than FK228 in inhibiting in vivo HDAC activity, due to rapid inactivation in medium and serum. Thus, FK228 serves as a stable prodrug to inhibit class I enzymes and is activated by reduction after uptake into the cells. The glutathione-mediated activation also implicates its clinical usefulness for counteracting glutathione-mediated drug resistance in chemotherapy.
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