Spirolides Isolated from Danish Strains of the Toxigenic Dinoflagellate Alexandrium ostenfeldii

MacKinnon, Shawna L.; Walter, John A.; Quilliam, Michael A.; Cembella, Allan; LeBlanc, Patricia; Burton, Ian W.; Hardstaff, W. R.; Lewis, N. I.

doi:10.1021/np050220w

Cited by 88 publications

(103 citation statements)

References 23 publications

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“…Spirolides A, C, and 13-desmethylspirolide C were isolated from A. ostenfeldii cultures (Nova Scotia, Canada) and their structures were determined (Hu et al, 2001). Subsequently, various spirolide analogues have been isolated and structurally characterized from A. ostenfeldii (Aasen et al, 2005;MacKinnon et al, 2006a;Roach et al, 2009;Ciminiello et al, 2010). Several unknown analogues have also been described together with known spirolides (Sleno et al, 2004;Almandoz et al, 2014;Tillmann et al, 2014;Rundberget et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Identification of gymnodimine D and presence of gymnodimine variants in the dinoflagellate Alexandrium ostenfeldii from the Baltic Sea

Harju

Koskela

Kremp

et al. 2016

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a b s t r a c tGymnodimines are lipophilic toxins produced by the marine dinoflagellates Karenia selliformis and Alexandrium ostenfeldii. Currently four gymnodimine analogues are known and characterized. Here we describe a novel gymnodimine and a range of gymnodimine related compounds found in an A. ostenfeldii isolate from the northern Baltic Sea. Gymnodimine D (1) was extracted and purified from clonal cultures, and characterized by liquid chromatographyetandem mass spectrometry (LCeMS/MS), nuclear magnetic resonance (NMR) spectroscopy, and liquid chromatographyehigh resolution mass spectrometry (LC eHRMS) experiments. The structure of 1 is related to known gymnodimines (2e5) with a six-membered cyclic imine ring and several other fragments typical of gymnodimines. However, the carbon chain in the gymnodimine macrocyclic ring differs from the known gymnodimines in having two tetrahydrofuran rings in the macrocyclic ring.

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Section: Introductionmentioning

confidence: 99%

Identification of gymnodimine D and presence of gymnodimine variants in the dinoflagellate Alexandrium ostenfeldii from the Baltic Sea

Harju

Koskela

Kremp

et al. 2016

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“…1) are a family of unique macrocyclic imine phycotoxins detected in North American and European coasts, first isolated from the digestive glands of mussels, scallops, and phytoplankton harvested from aquaculture sites (4-6). The dinoflagellate Alexandrium ostenfeldii has been associated to spirolide production (4,(7)(8)(9). Spirolides contain an unusual 5,5,6-bis-spirocetal moiety embedded within a 23-membered macrocycle along with a 6,7-spirocyclic imine structure that is found in related gymnodimines, pinnatoxins, and pteriatoxins (10).…”

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confidence: 99%

Structural determinants in phycotoxins and AChBP conferring high affinity binding and nicotinic AChR antagonism

Bourne

Radić

Aráoz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

147

194

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Spirolide and gymnodimine macrocyclic imine phycotoxins belong to an emerging class of chemical agents associated with marine algal blooms and shellfish toxicity. Analysis of 13-desmethyl spirolide C and gymnodimine A by binding and voltage-clamp recordings on muscle-type α1 2 βγδ and neuronal α3β2 and α4β2 nicotinic acetylcholine receptors reveals subnanomolar affinities, potent antagonism, and limited subtype selectivity. Their binding to acetylcholine-binding proteins (AChBP), as soluble receptor surrogates, exhibits picomolar affinities governed by diffusion-limited association and slow dissociation, accounting for apparent irreversibility. Crystal structures of the phycotoxins bound to Aplysia-AChBP (≈2.4Å) show toxins neatly imbedded within the nest of aromatic side chains contributed by loops C and F on opposing faces of the subunit interface, and which in physiological conditions accommodates acetylcholine. The structures also point to three major features: (i) the sequence-conserved loop C envelops the bound toxins to maximize surface complementarity; (ii) hydrogen bonding of the protonated imine nitrogen in the toxins with the carbonyl oxygen of loop C Trp147 tethers the toxin core centered within the pocket; and (iii) the spirolide bisspiroacetal or gymnodimine tetrahydrofuran and their common cyclohexene-butyrolactone further anchor the toxins in apical and membrane directions, along the subunit interface. In contrast, the sequence-variable loop F only sparingly contributes contact points to preserve the broad receptor subtype recognition unique to phycotoxins compared with other nicotinic antagonists. These data offer unique means for detecting spiroimine toxins in shellfish and identify distinctive ligands, functional determinants and binding regions for the design of new drugs able to target several receptor subtypes with high affinity.acetylcholine binding protein | marine phycotoxins | nicotinic acetylcholine receptor | pharmacological and structural analyses | seafood poisoning

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“…Alexandrium ostenfeldii I peruvianum has been found in the United States (Gribble et al 2005) and in New Zealand (Mackenzie 2004). In Europe, it has been identified along the Emilia Romagna coasts in the Italian part of the Adriatic Sea (Ciminiello et al 2006), in Ireland (Touzet et al 2008), in Scotland (John et al 2003), and in Denmark (MacKinnon et al 2006). Furthermore, SPXs' presence in shellfish has been reported in Italy (Pigozzi et al 2008), in Spain (Villar Gonzalez et al 2006) and in Norway (Aasen et al 2005).…”

Section: Spirolides (Spxs)mentioning

confidence: 97%

Cyclic imines, as emerging marine toxins: Chemical properties, distribution, toxicological aspects and detection methods

Chatzianastasiou¹,

Katikou²,

Zacharaki³

et al. 2017

J Hellenic Vet Med Soc

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Shellfish and, specifically, bivalve molluscs are a food commodity of great nterest for both commercial and public health reasons. They consume microalgae from surrounding waters, which are generally beneficial for aquaculture, but they comprise certain toxin-producing species. These species produce marine toxins which, via the filter-feeding mechanism of bivalve molluscs, accumulate in their tissues. This accumulation is more intense andmore dangerous for public health during the so-called periods of Harmful Algal Blooms (HABs) when the microalgal population grows. According to their chemical structure, marine toxins are classified into 8 groups, one of which is the cyclic imines. These lipophilic toxins were accidentally discovered during routine bioassays for the detection of other lipophilic marine toxins due to the induction of neurological symptoms and acute death in mice. They include the following subgroups: Spirolides (SPX), gymnodimines (GYM), pinnatoxins (PnTX), pteriatoxins (PtTX), prorocentrolides and spiro-prorocentrimines. The European Union (EU) is more concerned about the first three subgroups, because, in contrast with the latter three, they have already been detected in Europe or there is strong evidence supporting their presence. Spirolides are produced by the dmof\a.ge\\ate Alexandrìum ostenfeldii/peruvianum, gymnodimines by the dinoflagellate Karenia selliformis and pinnatoxins by a peridinoid dinoflagellate recently described in the new genus Vulcanodinium spp.. Although there is insufficient information regarding the geographical distribution of cyclic imines, the fact that they have been detected on multiple occasions in European waters, in combination with their aforementioned acute toxicity in mice after intraperitoneal injection, has established them, at least within the EU, as a topic of profound scientific research. In spite of their acute toxicity in mice, no incident of human intoxication has been attributed to cyclic imines. Presently, the EU has neither set any Maximum Permissible Limits for the concentration of cyclic imines in shellfish nor appointed any reference method for their detection and quantification. Currently, the methods applied are biological, biochemical and chemical. The biological method is a bioassay, which is conducted via the intraperitoneal injection of mice with an extract containing the compound under examination and it detects total toxicity. This properly is essential for the detection of unknown toxins, but the use of laboratory animals raises serious ethical concerns and animal welfare issues. The biochemical method is based on competition between cyclic imines and a fluorescently labelled compound for binding to receptors of the electric ray Torpedo marmorata. Finally, in respect of chemical methods, liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) is the most significant method because it is fast, of high repeatability and specificity.

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Spirolides Isolated from Danish Strains of the Toxigenic Dinoflagellate Alexandrium ostenfeldii

Cited by 88 publications

References 23 publications

Identification of gymnodimine D and presence of gymnodimine variants in the dinoflagellate Alexandrium ostenfeldii from the Baltic Sea

Identification of gymnodimine D and presence of gymnodimine variants in the dinoflagellate Alexandrium ostenfeldii from the Baltic Sea

Structural determinants in phycotoxins and AChBP conferring high affinity binding and nicotinic AChR antagonism

Cyclic imines, as emerging marine toxins: Chemical properties, distribution, toxicological aspects and detection methods

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