Self-Association of Okadaic Acid upon Complexation with Potassium Ion

Abstract

Okadaic acid (OA) is a toxin responsible for diarrhetic shellfish poisoning and is an extremely useful tool for studying processes that are regulated by phosphorylation, although the exact mechanism of action is still undetermined. We report on a study that proved the existence of OA in an unusual dimeric form when complexed with potassium ion. The proposed structure of this dimer is based on spectroscopic and conformational studies.

Belizeanic Acid: A Potent Protein Phosphatase 1 Inhibitor Belonging to the Okadaic Acid Class, with an Unusual Skeleton

“…The chirality of C‐16 and C‐19 was then adapted to build the four possible diastereoisomers and the resulting structures were used as the starting point for the conformational searches. Based on previous results obtained in our laboratory with these kinds of molecules,17, 18 these consisted of four independent searches with the MMFF94s19 force field as implemented in MacroModel 8.520 using the generalised Born/surface area (GBSA) water‐solvent model 21. Random searches of 100 000 MCMM steps were undertaken for each diastereoisomer to ensure that the potential energy surface was thoroughly explored using the TNCG algorithm.…”

Self-Association of Okadaic Acid: Structural and Pharmacological Significance

“…The aforementioned pharmacological results encouraged the authors to start a structural study of OAC in solution in order to explain the physiological importance of the complex [21]. Surprisingly, the NOESY spectrum of a 1 mg/mL sample of OAC recorded in CDCl 3 did not show cross-correlated signals contrary to what had been observed for OA.…”

“…The outcome was a model where the potassium ion-binding site was formed by three oxygen atoms attached to C-7 and C-8 of each OA monomer (Figure 2). The proposed structure therefore has a polar coordination site buried by a hydrophobic surface [21]. Thereafter, we considered the possibility that this structure could be a means of improving OA membrane permeability in accordance with the fact that the dimer was mainly found in CDCl 3 —a solvent that somehow mimics the lipid bilayer environment—and keeping in mind the bioactivity results obtained from experiments performed in tissues.…”

“…Structure proposed for the okadaic acid—potassium complex [21]. Each okadaic acid monomer is shown in a different color while K + is shown as a purple sphere.…”

Self-Assembly of Okadaic Acid as a Pathway to the Cell

“…These data prompted the authors to continue with the study, and subsequently, a model of the complex which consisted of two OA units and one potassium ion was proposed based on MS and NMR spectroscopy in combination with computational techniques. According to those results, potassium cations would be coordinated by two oxygens located at the spiro carbon C-8 and the oxygen present at C-7 giving a trigonal bipyramid binding geometry . Deeper analysis about the dimerization process is beyond the scope of this work.…”