Inhibition by new anthraquinone compounds, K-259-2 and KS-619-1, of calmodulin-dependent cyclic nucleotide phosphodiesterase.
K-259-2 and KS-619-1, novel anionic anthraquinone metabolites isolated from culture broth of microorganisms, inhibited activation of bovine brain phosphodiesterase induced by calmodulin (CaM), sodium oleate, or limited proteolysis with almost equal potency. The inhibition of calmodulin-activated phosphodiesterase (CaM-PDE) by K-259-2 or KS-619-1 was overcome by a higher concentration of CaM. Direct interaction of K-259-2 and KS-619-1 with CaM was confirmed through use of hydrophobic fluorescent probes. Kinetic analysis revealed that the inhibition of the trypsin-activated phosphodiesterase was competitively inhibited by K-259-2 or KS-619-1 with respect to cAMP. Addition of a lower amount of either phosphatidylserine or sodium oleate to the reaction mixture was efficacious in attenuating the inhibition of the CaM-PDE by W-7, chlorpromazine, trifluoperazine, compound 48/80, or R-24571 but, in contrast, had little or no effect on the inhibition by K-259-2 or KS-619-1. In conclusion, K-259-2 and KS-619-1, unlike so-called CaM antagonists, do not interact with phosphatidylserine or sodium oleate and it appears that these novel anthraquinone compounds inhibit the enzyme not only via CaM antagonism but possibly also by interacting directly with the enzyme.
Matsuda
Y
Y
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd, Japan.
Nakanishi
S
S
Nagasawa
K
K
Kase
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D006321:Heart / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*
D000880:Anthraquinones; D002147:Calmodulin; D010726:Phosphodiesterase Inhibitors; C054165:K 259-2; C054166:KS 619-1; C063189:K 259-3; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1