Inhibition of protein phosphatases-1 and -2A with acanthifolicin. Comparison with diarrhetic shellfish toxins and identification of a region on okadaic acid important for phosphatase inhibition.
Acanthifolicin (9,10-epithio-okadaic acid from Pandoras acanthifolium) inhibited protein phosphatase-1 (PP1) similarly to okadaic acid (IC50 = 20 nM and 19 nM, respectively) but was slightly less active against protein phosphatase-2A (PP2A) (IC50 = 1 nM and 0.2 nM, respectively). Methyl esterification of acanthifolicin sharply reduced its activity. PP2A was inhibited with an IC50 = 5.0 microM, whilst PP1 was inhibited less than 10% at 250 microM toxin. Okadaic acid methyl ester was similarly inactive whereas dinophysistoxin-1 (35-methyl okadaic acid) inhibited PP1/2A almost as potently as okadaic acid. Pure acanthifolicin/okadaic acid methyl ester may be useful as specific inhibitors of PP2A at 1-10 microM concentrations in vitro and perhaps in vivo. The data also indicate that a region on these toxins important for PP1/2A inhibition comprises the single carboxyl group.
Holmes
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National Research Council, Biotechnology Research Institute, Montreal, Québec, Canada.
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Schmitz
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D004988:Ethers, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D008387:Marine Toxins / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D019319:Okadaic Acid / Q000031:analogs & derivatives; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D011714:Pyrans / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004988:Ethers, Cyclic; D008387:Marine Toxins; D011714:Pyrans; D013141:Spiro Compounds; D019319:Okadaic Acid; C051904:dinophysistoxin 1; C065560:acanthifolicin; C066239:methyl okadaate; C066240:acanthifolicin methyl ester; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2