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

Marine Drugs

Yucheng Pang¹  Craig J. Forsyth¹  Chao Fang¹  Gregory J. Doucette²  Michael J. Twiner³  Christopher O. Miles⁴ 

[1] Department of Chemistry, The Ohio State University, Columbus, OH 43220, USA;Marine Biotoxins Program, Center for Coastal Environmental Health and Biomolecular Research, NOAA/National Ocean Service, Charleston, SC 29412, USA;School of Medicine, Wayne State University, Detroit, MI 48201, USA;Section for Chemistry and Toxicology, Norwegian Veterinary Institute, Oslo 0454, Norway;

关键词: cytotoxicity;    diarrheic shellfish poisoning (DSP);    dinophysistoxin (DTX);    harmful algal bloom (HAB);    okadaic acid (OA);    protein phosphatase (PP);    structure–activity relationship (SAR);   

DOI  :  10.3390/md14110207

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown