Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics
Corinna Bialojan,Akira Takai +1 more
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Kinetic studies showed that okadaic acid acts as a non-competitive or mixed inhibitor on the okadaIC acid-sensitive enzymes.Abstract:
The inhibitory effect of a marine-sponge toxin, okadaic acid, was examined on type 1, type 2A, type 2B and type 2C protein phosphatases as well as on a polycation-modulated (PCM) phosphatase. Of the protein phosphatases examined, the catalytic subunit of type 2A phosphatase from rabbit skeletal muscle was most potently inhibited. For the phosphorylated myosin light-chain (PMLC) phosphatase activity of the enzyme, the concentration of okadaic acid required to obtain 50% inhibition (ID50) was about 1 nM. The PMLC phosphatase activities of type 1 and PCM phosphatase were also strongly inhibited (ID50 0.1-0.5 microM). The PMCL phosphatase activity of type 2B phosphatase (calcineurin) was inhibited to a lesser extent (ID50 4-5 microM). Similar results were obtained for the phosphorylase a phosphatase activity of type 1 and PCM phosphatases and for the p-nitrophenyl phosphate phosphatase activity of calcineurin. The following phosphatases were not affected by up to 10 microM-okadaic acid: type 2C phosphatase, phosphotyrosyl phosphatase, inositol 1,4,5-trisphosphate phosphatase, acid phosphatases and alkaline phosphatases. Thus okadaic acid had a relatively high specificity for type 2A, type 1 and PCM phosphatases. Kinetic studies showed that okadaic acid acts as a non-competitive or mixed inhibitor on the okadaic acid-sensitive enzymes.read more
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Metabolic transformation of dinophysistoxin-3 into dinophysistoxin-1 causes human intoxication by consumption of O-acyl-derivatives dinophysistoxins contaminated shellfish.
Carlos García,Dominique Truan,Marcelo Lagos,Juan Pablo Santelices,Juan Carlos Díaz,Néstor Lagos +5 more
TL;DR: Evidence is given of metabolic transformation of 7-O-acyl-derivative dinophysistoxin-1 (DTX-3) into Dinophysistox1 ( DTX-1, Methyl-Okadaic acid) in intoxicated patients, responsible for the diarrheic symptoms and the intoxication syndrome showed by patients that consumed contaminated shellfish.
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Stimulatory effect of okadaic acid, an inhibitor of protein phosphatases, on nuclear envelope breakdown and protein phosphorylation in mouse oocytes and one-cell embryos.
TL;DR: Results of these experiments implicate protein phosphatases in the G2 to M transition of the cell cycle in both meiotic and mitotic cells.
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Evidence that the endogenous histone H1 phosphatase in HeLa mitotic chromosomes is protein phosphatase 1, not protein phosphatase 2A
TL;DR: Evidence from inhibitor studies is presented suggesting that the in vivo histone H1 phosphatase may be either PP1 or anotherosphatase with similar okadaic acid-sensitivity, but not PP2A.
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Dephosphorylation of the focal adhesion protein VASP in vitro and in intact human platelets
TL;DR: The accumulation of phosphorylated cAMP‐dependent protein kinase substrate(s) appears to account for inhibitory effects of okadaic acid on platelet function and indicates that the phosphorylation status of VASP in intact cells is regulated to a major extent by serine/ threonine protein phosphatases.
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Viewing serine/threonine protein phosphatases through the eyes of drug designers.
TL;DR: This review summarizes the current state of investigation of the small molecules that regulate the function of serine/threonine phosphatases, the challenges presented and also strategies to overcome these obstacles.
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