KS 504a

KS-504a inhibited bovine brain calmodulin-dependent cyclic nucleotide phosphodiesterase (CaM-PDE) with an IC50 value of 122 microM. The inhibition was reversed by a high concentration of calmodulin. Calmodulin-independent activities of the enzyme were not affected by the compound at the same concentration ranges. Ca2(+)-dependent interaction of the compounds with calmodulin was shown using hydrophobic fluorescence probes. These data indicated that the compound exerted its effects on CaM-PDE by interacting with calmodulin. KS-504a also inhibited other calmodulin-dependent enzymes at different concentration ranges; myosin light chain kinase was inhibited at the lowest concentrations with an IC50 value of 6.3 microM. The inhibition mechanism was competitive with respect to calmodulin and non-competitive to ATP.

Novel inhibitors of Ca2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase were isolated from the culture broth of a fungus, Mollisia ventosa KAC-1148. They were designated as KS-504a, KS-504b and KS-504d. A degradative product of KS-504a, called KS-504e, was also isolated and found to inhibit the enzyme. The 50% inhibitory concentration (IC50) values of KS-504a, KS-504b, KS-504d and KS-504e for bovine brain enzyme were 122, 109, greater than 500 and 139 microM, respectively.