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

Bourne, Yves; Radić, Zoran; Aráoz, Rómulo; Talley, Todd T.; Benoit, Évelyne; Servent, Denis; Taylor, Palmer; Molgó, Jordi; Marchot, Pierre

doi:10.1073/pnas.0912372107

Cited by 147 publications

(204 citation statements)

References 35 publications

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“…Structural studies of AChBP in complex with ligands have revealed a considerable flexibility in the so-called C-loop that closes in on agonists and forms a lid on the binding site. Thus, C-loop closure has been suggested to couple to channel activation (15,18,20,24), and it has even been suggested to be an important determinant for agonist efficacy (18,25).…”

mentioning

confidence: 99%

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

Rohde

Ahring

Jensen

et al. 2012

Journal of Biological Chemistry

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Background: Molecular features governing ␣4␤2 nAChRs efficacy have remained elusive. Results: Binding studies, electrophysiology, and structural data from co-crystallization with Ls-AChBP are reported for a series of ␣4␤2 agonists. Conclusion: Direct halogen bonds and an invariant Loop-C suggest that intersubunit bridge formation governs efficacy. Significance: The data provide a structural basis for understanding of efficacy levels at nAChRs.

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mentioning

confidence: 99%

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

Rohde

Ahring

Jensen

et al. 2012

Journal of Biological Chemistry

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“…toxicity. SPx and GYM interact with both muscle and neuronal nicotinic ACh receptors (nAChR) at subnanomolar concentrations (Bourne et al, 2010;Kharrat et al, 2008), and this interaction leads to respiratory paralysis in rats and mice treated with GYM (Kharrat et al, 2008). The question that needs to be answered is whether or not this mechanism also applies to humans and thus whether the data from the MBA are suitable for risk assessment for humans.…”

Section: Azaspiracid Shellfish Poisoning (Azp)mentioning

confidence: 99%

A roadmap for hazard monitoring and risk assessment of marine biotoxins on the basis of chemical and biological test systems

Daneshian

2013

ALTEX

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Summary Aquatic food accounts for over 40% of global animal food products, and the potential contamination with toxins of algal origin -marine biotoxins -poses a health threat for consumers. The gold standards to assess toxins in aquatic food have traditionally been in vivo methodssingle marine biotoxins or combinations of marine biotoxins and intoxication symptomatology as well as monitoring the "success" of controls implemented during fishery and aquaculture production, processing, and retailing. For this reason, a workshop was organized in ermatingen, Switzerland by the Center for Alternatives to Animal testing -europe (CAAteurope) within the framework of the transatlantic think tank for toxicology (t 4 ).In contrast to other food products where hygiene and potential contamination with microbes or mold toxins is the prime issue, the emphasis in aquatic products (shellfish and finfish) is, beyond viral and bacterial contaminations, primarily placed on potential contamination with marine biotoxins owing to the numerous and recurring human intoxications.The gold standards to assess toxins in aquatic food have traditionally been in vivo methods, i.e., the mouse and the rat bioassays. Besides the ethical issues of in vivo bioassays there are specific difficulties, e.g., different exposure route (i.p. versus oral), low inter-species comparability, high intra-species variability, and questionable extrapolation of quantitative risk to humans, thus highlighting the need for the development of more reliable detection and quantification methods. Based on this reasoning, the european Food Safety Authority (eFSA) advocates the use of an analytical method, i.e., LC-MS (Liquid Chromatography coupled Mass Spectrometry), as a substitute for in vivo bioassays for almost all classes of marine toxins. However, although lC-MS is a very sensitive method that has the advantages of being able to detect multiple toxins in a single analysis and being good for confirming the identity of toxins, the quality of quantitative analysis is dependent on the availability of calibration standards. While many new toxin structural analogues have been detected and identified using LC-MS, this technique -as with most other methods -is not good at detecting new toxin types. When new toxin analogues are detected but accurate standards are not yet available, only an approximate quantitation is possible using estimated response factors.For the purpose of risk assessment of food, however, it is imperative to focus on the possible adverse effects, independent of whether they stem from one toxin or a combination of toxins. As toxicity is defined by functional and structural changes of biological systems, the development of a human-relevant in vitro system for appropriate risk assessment of marine biotoxins in seafood stands to reason. Moreover, poor correlation of human intoxications, of acute symptomatology and long-term adverse effects, and of predictive in vitro, in vivo, and analytical detection methodologies of marine biotoxins stems not least from a...

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“…The possible cause for this toxicity is the intact cyclic imine-group that some SPXs and GYMs possess (Munday 2008, Bourne et al 2010). There is evidence that the neurotoxic action of SPXs and GYMs is based on their inhibition of both muscarinic and nicotinic acetylcholine receptors (mAChR and nAChR) in the central and peripheral nervous system (Munday 2008).…”

Section: Journal Of the Hellenic Veterinary Medical Society 201162(3)mentioning

confidence: 99%

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

Cited by 147 publications

References 35 publications

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

Intersubunit Bridge Formation Governs Agonist Efficacy at Nicotinic Acetylcholine α4β2 Receptors

A roadmap for hazard monitoring and risk assessment of marine biotoxins on the basis of chemical and biological test systems

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

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