A family of novel actin-inhibiting marine toxins.
1. We have examined the effects of marine toxins with a macrolide structure on actin. These toxins include mycalolide B, aplyronine A and bistheonellide A. 2. Measuring actin polymerization by monitoring fluorescent intensity of pyrenyl-actin, mycalolide B did not accelerate the actin polymerization but quickly depolymerized F-actin. In contrast, cytochalasin D, which inhibits actin polymerization by binding to the barbed end of F-actin, accelerated actin nucleation and depolymerized F-actin at a slower rate. 3. Analysing the kinetics of depolymerization by monitoring the rate of spontaneous depolymerization of F-actin under the unpolymerizable state or the rate of polymerization where F-actin was seeded as a nucleus, mycalolide B was suggested to sever F-actin. 4. The relationship between the concentration of total actin and F-actin at different concentrations of mycalolide B suggests that mycalolide B forms a 1:1 complex with G-actin. Viscometry and electron microscopic observations further suggest that the actin filament was depolymerized by mycalolide B. Furthermore, mycalolide B suppressed actin-activated myosin Mg(2+)-ATPase activity, although cytochalasin D did not. Aplyronine A has similar effects on actin. 5. Bistheonellide A also depolymerized F-actin and sequestered G-actin by forming a 1:2 complex with G-actins, but, its severing effect was not detected. We conclude that mycalolide B, aplyronine A and bistheonellide A are novel types of actin-depolymerizing agents, the mechanism of action of which is different from that of cytochalasin D. These structurally related marine toxins may be categorized as 'actin depolymerizing macrolides' and may serve as novel pharmacological tools for analysing actin-mediated cell functions.
Saito
S
S
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Japan.
Karaki
H
H
D000199:Actins / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D008387:Marine Toxins / Q000378:metabolism / Q000494:pharmacology*; D009218:Myosins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D011161:Porifera
D000199:Actins; D008387:Marine Toxins; D010080:Oxazoles; C080978:mycalolide B; D009218:Myosins