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PubMed2002

Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins.

The protein serine/threonine phosphatases constitute a unique class of enzymes that are critical for cell regulation, as they must counteract the activities of thousands of protein kinases in human cells. Uncontrolled inhibition of phosphatase activity by toxic inhibitors can lead to widespread catastrophic effects. Over the past decade, a number of natural product toxins have been identified that specifically and potently inhibit protein phosphatase-1 and 2A. Amongst these are the cyanobacteria-derived cyclic heptapeptide microcystin-LR and the polyether fatty acid okadaic acid from dinoflagellate sources. The molecular mechanism underlying potent inhibition of protein phosphatase-1 by these toxins is becoming clear through insights gathered from diverse sources. These include: 1. Comparison of structure-activity relationships amongst the different classes of toxins. 2. Delineation of the structural differences between protein phosphatase-1 and 2A that account for their differing sensitivity to toxins, particularly okadaic acid and microcystin-LR. 3. Determination of the crystal structure of protein phosphatase-1 with microcystin-LR, okadaic acid and calyculin bound. 4. Site-specific mutagenesis and biochemical analysis of protein phosphatase-1 mutants. Taken together, these data point to a common binding site on protein phosphatase-1 for okadaic acid, microcystin-LR and the calyculins. However, careful analysis of these data suggest that each toxin binds to the common binding site in a subtly different way, relying on distinct structural interactions such as hydrophobic binding, hydrogen bonding and electrostatic interactions to different degrees. The insights derived from studying the molecular enzymology of protein phosphatase-1 may help explain the different sensitivities of other structurally conserved protein serine/theonine phosphatases to toxin inhibition. Furthermore, studies on the binding of structurally diverse toxins at the active site of protein phosphatase-1 are leading to a clearer understanding of potential enzyme-substrate interactions in this important class of cell regulatory proteins.

Humans↗
PubMed1998

[Algal toxins, inhibitors of serine/threonine phosphatases].

Under certain environmental conditions, marine and freshwater phytoplankton may produce phycotoxins inhibitors of serine/thréonine protein phosphatases 1, 2A and 3. In the marine environment, dinoflagellates produce fatty polyethers: okadaic acid and its derivatives, the dinophysistoxins, which accumulate in shellfish and can cause diarrhetic shellfish poisoning (DSP) when ingested. In freshwater, the toxins are microcystins and nodularin, 7 or 5 amino acid cyclic peptides and are hepatotoxic. These toxins have caused massive poisoning of wild animals or domestic livestock and now are a health threat for humans through use of drinking and recreation water. Moreover, all these toxins are potent tumor promoters but belong to a new class, different from the TPA class, because they do not act on Protein Kinase C. Although the mutagenicity Ames test responds negatively, several results show their genotoxic potential, and therefore they are a health hazard through chronic exposition to low doses. Finally, okadaic acid, through its easy penetration in all cellular types can be used as a tool to study mechanisms involved in protein phosphorylation/dephosphorylation processes.

Animals↗
PubMed1999

Molecular mechanisms underlying inhibition of protein phosphatases by marine toxins.

The protein serine/threonine phosphatases constitute a unique class of enzymes that are critical regulatory enzymes as they must counteract the activities of thousands of protein kinases in human cells. Uncontrolled inhibition of phosphatase activity by toxic inhibitors can lead to widespread catastrophic effects. Over the past decade, a number of natural product toxins have been identified which specifically and potently inhibit protein phosphatase-1 and -2A. Among these are the cyanobacteria-derived cyclic heptapeptide microcystin-LR and the polyether fatty acid okadaic acid from dinoflagellate sources. The molecular mechanism of the potent inhibition of protein phosphatase-1 by these toxins is becoming clear through insights gathered from diverse sources. These include: 1. Comparison of structural variants of the toxins, 2. Delineating the structural differences between protein phosphatase-1 and -2A accounting for their differing sensitivity to okadaic acid, 3. Determination of the crystal structure of protein phosphatase-1 with microcystin-LR bound and, most recently, 4. Mutagenesis of protein phosphatase-1. Taken together, these data point to a common binding site on protein phosphatase-1 for okadaic acid and microcystin-LR. However, the details of these data suggest that each toxin binds to the common site in a subtly different way, relying on common structural interactions to different degrees. Finally, the insights derived from protein phosphatase-1 may help explain different sensitivities of other protein serine/threonine phosphatases to toxin inhibition due to the high degree of structural conservation among many members of this enzyme family.

Animals↗
PubMed2005

Potent neurotoxic action of the shellfish biotoxin yessotoxin on cultured cerebellar neurons.

Yessotoxin (YTX) and its analogues are disulphated polyether compounds of increasing occurrence in seafood. The biological effects of these algal toxins on mammals and the risk associated to their ingestion have not been clearly established. We have used primary cultures of rat cerebellar neurons to investigate whether YTX affected survival and functioning of central nervous system neurons. Exposure to YTX (> or =25 nM) caused first (approximately 8 h) weakening, granulation, and fragmentation of neuronal network, and later (approximately 48 h) complete disintegration of neurites and extensive neuronal death, with a significant decrease in the amount of filamentous actin. The concentration of YTX that reduced by 50% the maximum neuronal survival (EC50(48)) was approximately 20 nM. Lower toxin concentrations (approximately 15 nM) also caused visible signs of toxicity affecting neuronal network primarily. Removal of YTX after 5 h exposure delayed the onset of neurotoxicity but did not prevent neuronal degeneration and death. YTX induced a two-fold increase in cytosolic calcium that was prevented by the voltage-sensitive calcium channel antagonists nifedipine and verapamil. These antagonists were, however, completely ineffective in reducing neurotoxicity. Voltage-sensitive sodium channel antagonists saxitoxin and nefopam, and the NMDA receptor antagonist MK-801 also failed to prevent YTX neurotoxicity. Neuronal death by YTX involved typical hallmarks of apoptosis and required the synthesis of new proteins. Our data suggest neuronal tissue to be a vulnerable biological target for YTX. The potent neurotoxicity of YTX we report raises reasonable concern about the potential risk that exposure to YTX may represent for neuronal survival in vivo.

Animals↗
PubMed1993

The polyether Bistramide A affects the calcium sensitivity of the contractile proteins in frog atrial heart muscle.

The effects of Bistramide A, a new toxin isolated from the Urochordate Lissoclinum bistratum Sluiter have been studied on the mechanical activity of frog heart atrial muscle preparations. The peak tension of isolated trabeculae was sensitive to nanomolar concentrations of Bistramide A. Lineweaver-Burk relationships suggest that Bistramide A competes with Ca for a common site. In voltage-clamped trabeculae, the toxin inhibited both the cadmium-sensitive Ca current and the phasic component of the tension with a dissociation constant of 3.3 microM and a stoichiometry of 2. Bistramide A decreased the isometric tension of skinned fibres in a dose-dependent manner with a dissociation constant of 400 nM and a stoichiometry of 2. The toxin reduced the maximum Ca activated force and decreased the sensitivity of the contractile proteins to Ca. The data suggest that Bistramide A decreases the Ca-sensitivity of contractile proteins prior to blocking the Ca current.

Acetamides↗
PubMed2004

Highly cytotoxic metabolites from the culture supernatant of the temperate dinoflagellate Protoceratium cf. reticulatum.

In the course of our search for antitumor compounds in dinoflagellates, the culture broths of two strains of Protoceratium cf. reticulatum showed extremely potent cytotoxicity against human tumor cell lines. The four equally active principles, named protoceratins I (1), II (2), III (3), and IV (4), were purified and their structures were studied. The major principle, protoceratin I (1), proved to be identical with 2-homoyessotoxin, a well-known shellfish toxin. Protoceratins II (2), III (3), and IV (4) were determined to be di-, mono-, and triarabinoside of 1, respectively. They are the first examples of glycosides of dinoflagellate polyethers.

Animals↗
PubMed1989

Histopathological studies on experimental marine toxin poisoning--III. Morphological changes in the liver and thymus of male ICR mice induced by goniodomin A, isolated from the dinoflagellate Goniodoma pseudogoniaulax.

The i.p. LD50 values of goniodomin A, a novel polyether macrolide, in male ICR mice were 1.2 and 0.7 mg/kg at 24 and 48 hr, respectively. Histologically, perihepatitis, non-fatty vacuoles in the hepatocytes, central necrosis of the liver and massive necrosis of lymphocytes, in the cortical layer of the thymus, were prominent.

Animals↗
PubMed1998

Okadaic acid-induced lens epithelial cell apoptosis requires inhibition of phosphatase-1 and is associated with induction of gene expression including p53 and bax.

It is well established that phosphorylation and dephosphorylation are key cellular events which regulate important metabolic activities such as gene expression, cell cycle progression, and apoptosis. The polyether fatty acid, okadaic acid has been shown previously to activate apoptosis in a variety of cell lines. Although this marine sponge toxin is known to inhibit protein phosphatase (PP)-2A and PP-1, it is not certain in most cases whether inhibition of PP-1 or PP-2A is necessary to activate apoptosis. Furthermore, it is not clear how inhibition of these phosphatases leads to apoptosis. Here we present evidence that inhibition of PP-2A by okadaic acid does not activate apoptosis in the lens system. However, when PP-1 is inhibited by okadaic acid, rabbit lens epithelial cells undergo rapid apoptosis. Associated with this process is the several-fold up-regulation of the tumor suppressor gene p53 and the pro-apoptotic gene bax at both mRNA and protein levels. Analyses of the temporal pattern of expression of the two genes reveal that the up-regulation is maximized in a few hours after treatment with okadaic acid, when the majority of the treated cells become committed to apoptosis. A brief treatment of the cells with a protein synthesis inhibitor can abolish okadaic acid-induced up-regulation of both P53 and Bax proteins. Concomitant with this inhibition, okadaic acid-induced apoptosis is also temporarily blocked. These results suggest that okadaic acid-induced expression of p53, bax, and other genes are necessary for the activation of the apoptotic programs in lens systems.

Animals↗
PubMed2002

Analysis of toxin profiles in three different fish species causing ciguatera fish poisoning in Guadeloupe, French West Indies.

A grey snapper (Lutjanus griseus), a grouper (Serranidae) and a black jack (Caranx lugubris) were implicated in three different ciguatera poisonings in Guadeloupe, French West Indies. A mouse bioassay indicated toxicity for each specimens: 0.5-1, > or = 1 and > 1 MUg g(-1), respectively. After purification by gel filtration chromatography, the samples were analysed by high-performance liquid chromatography coupled to mass spectrometry (LC-MS). The toxin profiles differ from one fish to another. C-CTX-1 was detected at 0.24, 0.90 and 13.8 ng g(-1) flesh in the snapper, grouper and jack, respectively. It contributed only to part of the whole toxicity determined by the mouse bioassay. Other toxins identified were C-CTX-2 (a C-CTX-1 epimer), three additional isomers of C-CTX-1 or-2, and five ciguatoxin congeners (C-CTX-1127, C-CTX-1143 and its isomer C-CTX-1143a, and C-CTX-1157 and its isomer C-CTX-1157b). Putative hydroxy-polyether-like compounds were also detected in the flesh of the grouper with [M+ + H]+ ions at m/z 851.51, 857.50, 875.51, 875.49 and 895.54 Da. Some of these compounds have the same mass range as some known dinoflagellate toxins. In conclusion, this study confirms the usefulness of LC-MS analysis to determine the ciguatoxins levels and the toxin profile in fish flesh hazardous to humans.

Adult↗
PubMed2003

Identification of slow and fast-acting toxins in a highly ciguatoxic barracuda (Sphyraena barracuda) by HPLC/MS and radiolabelled ligand binding.

A barracuda implicated in ciguatera fish poisoning in Guadeloupe was estimated to have an overall flesh toxicity of 15 MUg/g using mouse bioassay. A lipid soluble extract was separated into two toxic fractions, FrA and FrB, on a LH20 Sephadex column eluted with dichloromethane/methanol (1:1). When intraperitoneal injected into mice, FrA provoked symptoms characteristic of slow-acting ciguatoxins, whereas FrB produced symptoms indicative of fast-acting toxins (FAT). High performance liquid chromatography/mass spectrometry/radio-ligand binding (HPLC/MS/RLB) analysis confirmed the two fractions were distinct, because only a weak overlap of some compounds was observed. HPLC/MS/RLB analysis revealed C-CTX-1 as the potent toxin present in FrA, and two coeluting active compounds at m/z 809.43 and 857.42 in FrB, all displaying the characteristic pattern of ion formation for hydroxy-polyethers. Other C-CTX congeners and putative hydroxy-polyether-like compounds were detected in both fractions, however, the RLB found them inactive. C-CTX-1 accounted for > 90% of total toxicity in this barracuda and was confirmed to be a competitive inhibitor of brevetoxin binding to voltage-sensitive sodium channels (VSSCs) with a potency two-times lower than P-CTX-1. However, FAT active on VSSCs and < 900 Da were suspected to contribute to the overall toxicity.

Animals↗
PubMed2004

Marine toxins and nonmarine toxins: convergence or symbiotic organisms?

Bioactive marine natural products occur only rarely in nonmarine sources. The converse also is true. Divergent evolutionary pathways for the biosynthesis of bioactive secondary metabolites seem to be the rule. Marine biosynthetic pathways lead to a wide variety of different structural classes, among which polyethers, macrolides, terpenes, unusual amino acids/peptides, and alkaloids are notable. Nonmarine biosynthetic pathways also lead to a similar wide variety of structural classes. However, the structures are usually quite different from the marine analogues. The alkaloids of plants are notable, but again there appears little convergence between the marine and nonmarine alkaloids. However, tetrodotoxin, a remarkable, highly polar, marine alkaloid, does occur in various amphibians. The occurrence and possible origin of tetrodotoxin and congeners, including chiriquitoxin, and of the saxitoxin analogue zetekitoxin in amphibians are reviewed.

Alkaloids↗
PubMed1992

Analysis of Acanthurus triostegus for marine toxins by the stick enzyme immunoassay and mouse bioassay.

The herbivorous convict tang or surgeon fish, Acanthurus triostegus, collected at different locations in the Hawaiian islands, was analyzed for toxicity using a mouse bioassay and a stick enzyme immunoassay (S-EIA) developed to detect ciguatoxin and closely related polyethers. Results of the S-EIA test indicated that about 94% of the samples gave negative readings, while 6% of the fish were positive and thus considered toxic. Fish samples from each location were pooled and the flesh and viscera were successively extracted with hexane, methanol, and water and tested in a mouse bioassay. About one-third of the methanol soluble fractions killed mice within 20 min, 70% killed within 4 hr, and 85% killed within 48 hr. About 40% of the hexane-soluble fractions killed mice within 24 hr and 55% killed within 48 hr. The water-soluble extracts of the flesh and viscera of fish taken from three locations showed relatively high toxicity. Common symptoms for all fractions included convulsions and jumping (especially just prior to death), respiratory distress, hind leg to complete paralysis, loss of body tone, and tremors. Analysis of the data suggests that in the flesh and viscera of A. triostegus there are at least three different nervous system-type toxins, most of which did not appear to react to the S-EIA test.

Animals↗
PubMed2006

Lysosomes as the target of yessotoxin in invertebrate and vertebrate cell lines.

The toxic effects of the algal polyether phycotoxin yessotoxin (YTX) are studied in the insect fat body IPLB-LdFB and the mouse fibroblast NIH3T3 cell lines. Our experiments confirm the cytotoxic action exerted by the toxin in both insect and mammalian cells, but morphological observations, TUNEL experiments and electrophoretic evalution of DNA integrity failed to evidence a clear pro-apoptotic role for YTX. In both IPLB-LdFB and NIH3T3 cell lines, neutral red and acridine orange stainings, together with evaluation of acid phosphatase activity demonstrate that YTX first damages lysosomal vesicles. This is then followed by a progressive depolymerization of actin microfilaments, as shown by phalloidin fluorescent immunostaining. Overall, our data identify in early lysosomal damage and the subsequent cytoskeletal disruption two common steps related to YTX toxicity towards metazoan cells.

3T3 Cells↗
PubMed2002

Total synthesis of (-)-gambierol.

The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).

Ciguatoxins↗
PubMed1996

Okadaic acid induces changes in the organization of F-actin in intestinal cells.

Okadaic acid, a polyether fatty acid associated with diarrhetic seafood poisoning, is capable of inhibiting protein phosphatases 1 and 2A which are considered among the major protein phosphatases in the cytosol of mammalian cells. One of the substrates for these phosphatases has been reported to be the cytoskeleton. In this paper, we focused on the effects of okadaic acid in intestinal cells, the more physiological target for this toxin. By fluorescence and scanning electron microscopy, we evidenced a dose- and time-dependent effect on F-actin which preceded any detectable change of tubulin and vimentin network. By a flow cytometric approach, we observed that plasma membrane permeability and transmembrane potential, two indicators of early cell damage or activation, respectively, remained unaffected in intoxicated cells. The present data strongly support the theory that actin is one of the main cytosolic targets for the phosphatases inhibited by okadaic acid in intestinal cells.

Actins↗
PubMedDate not supplied

A simple membrane immunobead assay for detecting ciguatoxin and related polyethers from human ciguatera intoxication and natural reef fishes.

A simple membrane immunobead assay (MIA) for detecting ciguatoxin (CTX) and related polyethers directly from fish tissue is presented. A membrane laminated onto a solid plastic support is immersed with a piece of fish tissue in methanol. The membrane is thoroughly dried and placed into an immunobead suspension containing polystyrene particles coated with monoclonal antibody to CTX (MAb-CTX). Two beads of different diameter and color are used. The color intensity of the membrane is related to the concentration of the toxin bound to the membrane. Twelve of 13 fish implicated in human ciguatera fish poisoning showed borderline or positive responses in the assay. A Sphyraena barracuda sample that tested negative with the MIA and was highly toxic with the mouse toxicity bioassay showed only weak CTX-like toxin activity in the guinea pig atrial assay, indicating that the major toxin in the sample was not CTX-like. Examination of 154 routinely caught reef fish from Hawaii, Kosrae, and Kwajalein by MIA found 132 (86%) negative and 8 (5%) positive for CTX, with 14 (9%) giving a borderline response. Fish from Hawaii showed a higher frequency of borderline or positive responses than those from Kosrae and Kwajalein, probably because several species of fish from several islands of Hawaii were tested, whereas only one species from a single area was examined from each of the islands of Kosrae and Kwajalein.

Animals↗
PubMed1997

Okadaic acid and its interaction with sodium, potassium, magnesium and calcium ions: complex formation and transport across a liquid membrane.

Okadaic acid, a macrocyclic polyether compound, was shown to mediate the transfer of Na+, K+, Mg2+ and Ca2+ ions from aqueous solution to an organic phase, with a preference for Na+ ions. A kinetic study of the transport of these ions across a liquid membrane showed that the Na+ ion was more rapidly transported than the other ions and that the Na+ ion flux was dependent on the okadaic acid concentration.

Biological Transport↗
PubMed1987

Gambierdiscus toxicus in gut content of the surgeonfish Ctenochaetus strigosus (herbivore) and its relationship to toxicity.

Flesh of surgeonfish, Ctenochaetus strigosus, obtained from corresponding catches of C. strigosus implicated in ciguatera poisoning outbreaks was examined for ciguatoxin and related polyethers by the stick test enzyme immunoassay. Simultaneously, gut contents of the fish were examined under phase microscopy for the presence of Gambierdiscus toxicus. Eighty-seven per cent of the fish were stick EIA positive, while 98% were positive for G. toxicus in gut contents. The data obtained suggest a relationship between G. toxicus in gut content and tissue toxicity levels. This is in agreement with previous studies which demonstrated a relationship between G. toxicus in fish gut content and toxicity of the flesh to animals and humans.

Animals↗