Characterization of natural toxins with inhibitory activity against serine/threonine protein phosphatases.
Recent studies suggest that the ability to inhibit the activity of certain serine/threonine protein phosphatases underlies the toxicity of several natural compounds including: okadaic acid, microcystin-LR, nodularin, calyculin A and tautomycin. To characterize further the actions of these toxins, this study compares the inhibitory effects of okadaic acid, chemical derivatives of okadaic acid, microcystin-LR, microcystin-LA, nodularin, calyculin A and tautomycin on the activity of serine/threonine protein phosphatases types 1 (PP1), 2A (PP2A) and a recently identified protein phosphatase purified from bovine brain (PP3). This study shows that, like PP1 and PP2A, the activity of PP3 is potently inhibited by okadaic acid, both microcystins, nodularin, calyculin A and tautomycin. Further characterization of the toxins employing the purified catalytic subunits of PP1, PP2A and PP3 under identical experimental conditions indicates that: (a) okadaic acid, microcystin-LR, and microcystin-LA inhibit PP2A and PP3 more potently than PP1 (order of potency PP2A > PP3 > PP1); (b) nodularin inhibits PP1 and PP3 at a similar concentration that is slightly higher than that which affects PP2A, and (c) both calyculin A and tautomycin show little selectivity among the phosphatases tested. This study also shows that the chemical modification of the (C1) carboxyl group of okadaic acid can have a profound influence on the inhibitory activity of this toxin. Esterification of okadaic acid, producing methyl okadaate, or reduction, producing okadaol, greatly decreases the inhibitory effects against all three enzymes tested. Further reduction, producing 1-nor-okadaone, or acetylation, producing okadaic acid tetraacetate, results in compounds with no inhibitory activity. In contrast, the substitution of alanine (-LA) for arginine (-LR) in microcystin has no apparent effect on the inhibitory activity against PP1, PP2A or PP3.
Honkanen
R E
RE
Department of Biochemistry, University of South Alabama, Mobile 36688.
Codispoti
B A
BA
Tse
K
K
Boynton
A L
AL
Honkanan
R E
RE
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000633:toxicity; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004951:Esterification; D004988:Ethers, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D008387:Marine Toxins / Q000737:chemistry / Q000633:toxicity*; D052998:Microcystins; D019319:Okadaic Acid; D010080:Oxazoles / Q000737:chemistry / Q000633:toxicity; D010084:Oxidation-Reduction; D010456:Peptides, Cyclic / Q000737:chemistry / Q000633:toxicity; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010764:Phosphorylase Kinase / Q000037:antagonists & inhibitors; D010763:Phosphorylase b / Q000037:antagonists & inhibitors; D011714:Pyrans; D011817:Rabbits; D013141:Spiro Compounds
D000935:Antifungal Agents; D004988:Ethers, Cyclic; D008387:Marine Toxins; D052998:Microcystins; D010080:Oxazoles; D010456:Peptides, Cyclic; D011714:Pyrans; D013141:Spiro Compounds; C063998:nodularin; C053079:tautomycin; D019319:Okadaic Acid; C059041:calyculin A; D010763:Phosphorylase b; D010764:Phosphorylase Kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; C057862:cyanoginosin LR