Calmodulin antagonistic action of KS-504a, a novel metabolite of the fungus Mollisia ventosa.
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.
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
S
S
Nakanishi
K
K
Kuroda
K
K
Osawa
H
H
Kase
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001203:Ascomycota / Q000378:metabolism*; D001921:Brain / Q000201:enzymology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D003517:Cyclopentanes / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005456:Fluorescent Dyes; D007700:Kinetics; D009206:Myocardium / Q000201:enzymology; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000494:pharmacology
D002147:Calmodulin; D003517:Cyclopentanes; D005456:Fluorescent Dyes; C063093:KS 504a; D009219:Myosin-Light-Chain Kinase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D014357:Trypsin; D000252:Calcium-Transporting ATPases