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

Daranas, Antonio Hernández; Cruz, Patricia G.; Creus, Alberto Hernández; Norte, Manuel; Fernández, José J.

doi:10.1021/ol701687m

Cited by 15 publications

(11 citation statements)

References 17 publications

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“…Daranas et al . [268] found that the OA molecules can pass lipid bilayers, and consequently cell membranes, after the acid ions are partially neutralized by forming dimers with potassium atoms. Blue mussels ( M. edulis ) can take up azaspiracids (AZAs), which are slightly more apolar than OA, mainly via the gill, but the toxins may have been adsorbed on the surface of microflagellates given as food [269].…”

Section: Uptake Accumulation Detoxification and Enzymatic Transmentioning

confidence: 99%

Dinophysis Toxins: Causative Organisms, Distribution and Fate in Shellfish

et al. 2014

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Several Dinophysis species produce diarrhoetic toxins (okadaic acid and dinophysistoxins) and pectenotoxins, and cause gastointestinal illness, Diarrhetic Shellfish Poisoning (DSP), even at low cell densities (<103 cells·L−1). They are the main threat, in terms of days of harvesting bans, to aquaculture in Northern Japan, Chile, and Europe. Toxicity and toxin profiles are very variable, more between strains than species. The distribution of DSP events mirrors that of shellfish production areas that have implemented toxin regulations, otherwise misinterpreted as bacterial or viral contamination. Field observations and laboratory experiments have shown that most of the toxins produced by Dinophysis are released into the medium, raising questions about the ecological role of extracelular toxins and their potential uptake by shellfish. Shellfish contamination results from a complex balance between food selection, adsorption, species-specific enzymatic transformations, and allometric processes. Highest risk areas are those combining Dinophysis strains with high cell content of okadaates, aquaculture with predominance of mytilids (good accumulators of toxins), and consumers who frequently include mussels in their diet. Regions including pectenotoxins in their regulated phycotoxins will suffer from much longer harvesting bans and from disloyal competition with production areas where these toxins have been deregulated.

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Section: Uptake Accumulation Detoxification and Enzymatic Transmentioning

confidence: 99%

Dinophysis Toxins: Causative Organisms, Distribution and Fate in Shellfish

et al. 2014

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“…However, such measurements do not discard the existence of minor populations of monomers and/or tetramers. Considering that we have successfully used scanning tunneling microscopy (STM) to confirm the existence of dimeric forms of OA [22], we decided to follow a similar approach to confirm the existence of its tetrameric forms. In order to do this, a gold plate was dipped into a methanol solution of OA (10 mg/mL) and as expected, a gold surface mainly covered by 40–45 Å particles that correspond to OA dimers (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…Using this technique it is possible to measure particle sizes, therefore it was feasible to differentiate between particles formed by one or two units of OA, therefore the formation the dimers mediated by K + ions was verified (Figure 3). Subsequently, a simplified model to study the transport of the toxin through a lipid bilayer was built separating two KCl aqueous solutions by a lipid bilayer [22]. One solution had the K + concentration that can be found in the intracellular medium (100 mM) while the other contained 0.5 mM of OA and 5 mM of the same electrolyte (equivalent to the extracellular concentration).…”

Section: Dimerization Of Okadaic Acid Overviewmentioning

confidence: 99%

Self-Association of Okadaic Acid: Structural and Pharmacological Significance

et al. 2013

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Okadaic acid (OA) has been an invaluable pharmacological tool in the study of cellular signaling. The great affinity of this polyether for its targets together with its high specificity to inhibit certain protein phosphatases enables the differential study of these proteins. Crystallographic structures of protein phosphatases in complex with OA show a 1:1 protein to toxin ratio. Nevertheless, it has been found that OA is able to self-associate under certain conditions although very little is known about the importance of this phenomenon. Here we review the available knowledge on the latter topic and we report on the existence of an unusual self-associated tetrameric form. The structure of these oligomers is proposed based on spectroscopic data and molecular modeling calculations.

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“…The hydrophobic groove is exposed at the surface. MCLR and TM have similar structures, with three features in common: a carboxyl group, a hydrophobic tail, and a large macrocyclic domain (26). MCLR binds to PP1 in such a way as to interact with three distinct regions of the surface: the metal‐binding site, the hydrophobic groove, and the edge of the C‐terminal groove near the active site.…”

Section: Discussionmentioning

confidence: 99%

Tyr306 near the C‐terminus of protein phosphatase‐1 affects enzyme stability and inhibitor binding

et al. 2011

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Previous deletion studies have suggested that Tyr306 has an important influence on the properties of protein phosphatase-1 (PP1). To test this inference, we constructed three site-directed mutants, PP1Y306A, PP1Y306K, and PP1Y306E. The specific activity of PP1Y306A was 3.5-fold higher than that of PP1wt, especially with K-R-Tp-I-R-R as substrate, and it also had a 13-fold higher Kcat and a 43-fold higher Kcat /Km . PP1Y306K and PP1Y306E, in that order, and were next in terms of increased activity. Use of the denaturant guanidine hydrochloride (GdnHCl) demonstrated that mutation of this site decreased enzyme stability. PP1Y306A and PP1Y306E lost all activity when incubated for 24 h in 0.6 M GdnHCl, and their fluorescence spectra confirmed the loss of stability. Because all three substitutions had a similar effect, we infer that the aromatic group of Tyr plays a crucial role in maintaining enzyme stability. Our results show that Tyr306 does affect the spatial conformation of the catalytic subunit of PP1 molecule. The IC50 of PP1Y306A for the inhibitor microcystin-LR was threefold higher than that of PP1wt, whereas those of PP1Y306E for tautomycin and norcantharidin were 15-fold and 10-fold higher, respectively. We conclude that Tyr306 plays an important role in enzyme stability and inhibitor binding.

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

Cited by 15 publications

References 17 publications

Dinophysis Toxins: Causative Organisms, Distribution and Fate in Shellfish

Dinophysis Toxins: Causative Organisms, Distribution and Fate in Shellfish

Self-Association of Okadaic Acid: Structural and Pharmacological Significance

Tyr306 near the C‐terminus of protein phosphatase‐1 affects enzyme stability and inhibitor binding

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