Nucleoside antibiotics are found as diverse groups of secondary metabolites of microbial origin. They include a variety of structural modifications of nucleosides and nucleotides, often leading to intricate molecules. Their biological activities are also wide ranging, including antibacterial, antifungal, antitrypanosomal, antitumor, antiviral, herbicidal, insecticidal, immunostimulating, and often immunosuppressive properties. It is not surprising that nucleoside antibiotics exhibit such diverse biological activities, because nucleosides and nucleotides play pleiotropic roles in most fundamental cellular metabolic pathways such as metabolite carriers, energy donors, secondary messengers, and co factors for various enzymes. Thus, not only nucleic acid synthesis but also protein synthesis, glycan synthesis, and glycoprotein synthesis are targets of nucleoside antibiotics. The protein kinases, key enzymes for cell proliferation and differentiation, also require nucleotides as phosphate donors.
Several groups have reported that okadaic acid (OA) and some other tight-binding protein phosphatase inhibitors including microcystin-LR (MCLR), calyculin-A and tautomycin prevent each other from binding to protein phosphatase 2A (PP2A). In this paper, we have introduced an improved procedure for examining to what extent the affinity of an enzyme for a labelled tight-binding ligand is reduced by binding of an unlabelled tight-binding, ligand to the enzyme. Using this procedure, we have analysed the dose-dependent reduction of PP2A binding of [24-3H]OA by addition of OA, MCLR, calyculin-A and tautomycin. The results indicate that the binding of the unlabelled inhibitors to the PP2A molecule causes a dramatic (10(6)-10(8)-fold) increase in the dissociation constant associated with the interaction of [24-3H]OA and PP2A. This suggests that OA and the other inhibitors bind to PP2A in a mutually exclusive manner. The protein phosphatase inhibitors may share the same binding site on the PP2A molecule. We have also measured values of the dissociation constant (Ki) for the interaction of these toxins with protein phosphatase 1 (PP1). For MCLR and calyculin-A, the ratio of the Ki value obtained for PP1 to that for PP2A was in the range 4-9, whereas it was 0.01-0.02 for tautomycin. The value of tautomycin is considerably smaller than that (0.4) calculated from previously reported Ki values.
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