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Mar. Drugs 2016, 14(11), 207; doi:10.3390/md14110207

Structure–Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins

School of Medicine, Wayne State University, Detroit, MI 48201, USA
Department of Natural Sciences, University of Michigan, Dearborn, MI 48128, USA
Marine Biotoxins Program, Center for Coastal Environmental Health and Biomolecular Research, NOAA/National Ocean Service, Charleston, SC 29412, USA
Department of Chemistry, The Ohio State University, Columbus, OH 43220, USA
Section for Chemistry and Toxicology, Norwegian Veterinary Institute, Oslo 0454, Norway
Current address: Bioduro, Innovation Building E No.29 Life Science Park Road, Changping District, Beijing 102206, China.
Current address: Ariad Pharmaceuticals, 26 Landsdowne St, Cambridge, MA 02139, USA.
Author to whom correspondence should be addressed.
Academic Editor: Paul Long
Received: 9 July 2016 / Revised: 7 August 2016 / Accepted: 31 October 2016 / Published: 4 November 2016
(This article belongs to the Collection Bioactive Compounds from Marine Plankton)
View Full-Text   |   Download PDF [831 KB, uploaded 4 November 2016]   |  


Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase (ser/thr PP) inhibitors. Phosphatases are important modulators of enzyme activity and cell signaling pathways. However, the interactions between the OA/DTX toxins and phosphatases are not fully understood. This study sought to identify phosphatase targets and characterize their structure–activity relationships (SAR) with these algal toxins using a combination of phosphatase activity and cytotoxicity assays. Preliminary screening of 21 human and yeast phosphatases indicated that only three ser/thr PPs (PP2a, PP1, PP5) were inhibited by physiologically saturating concentrations of DTX2 (200 nM). SAR studies employed naturally-isolated OA, DTX1, and DTX2, which vary in degree and/or position of methylation, in addition to synthetic 2-epi-DTX2. OA/DTX analogs induced cytotoxicity and inhibited PP activity with a relatively conserved order of potency: OA = DTX1 ≥ DTX2 >> 2-epi-DTX. The PPs were also differentially inhibited with sensitivities of PP2a > PP5 > PP1. These findings demonstrate that small variations in OA/DTX toxin structures, particularly at the head region (i.e., C1/C2), result in significant changes in toxicological potency, whereas changes in methylation at C31 and C35 (tail region) only mildly affect potency. In addition to this being the first study to extensively test OA/DTX analogs’ activities towards PP5, these data will be helpful for accurately determining toxic equivalence factors (TEFs), facilitating molecular modeling efforts, and developing highly selective phosphatase inhibitors. View Full-Text
Keywords: cytotoxicity; diarrheic shellfish poisoning (DSP); dinophysistoxin (DTX); harmful algal bloom (HAB); okadaic acid (OA); protein phosphatase (PP); structure–activity relationship (SAR) cytotoxicity; diarrheic shellfish poisoning (DSP); dinophysistoxin (DTX); harmful algal bloom (HAB); okadaic acid (OA); protein phosphatase (PP); structure–activity relationship (SAR)

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Twiner, M.J.; Doucette, G.J.; Pang, Y.; Fang, C.; Forsyth, C.J.; Miles, C.O. Structure–Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins. Mar. Drugs 2016, 14, 207.

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