Sulfo-Gambierones, Two New Analogs of Gambierone Produced by Gambierdiscus excentricus.
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ABSTRACT:
SUBMITTER: Yon T
PROVIDER: S-EPMC8703632 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gambierdiscus species are the producers of the marine toxins ciguatoxins and maitotoxins which cause worldwide human intoxications recognized as Ciguatera Fish Poisoning. A deep chemical investigation of a cultured strain of G. belizeanus, collected in the Caribbean Sea, led to the identification of a structural homologue of the recently described gambierone isolated from the same strain. The structure was elucidated mainly by comparison of NMR and MS data with those of gambierone and ascertained by 2D NMR data analyses. Gratifyingly, a close inspection of the MS data of the new 44-methylgambierone suggests that this toxin would actually correspond to the structure of maitotoxin-3 (MTX3, m/z 1039.4957 for the protonated adduct) detected in 1994 in a Pacific strain of Gambierdiscus and recently shown in routine monitoring programs. Therefore, this work provides for the first time the chemical identification of the MTX3 molecule by NMR. Furthermore, biological data confirmed the similar activities of both gambierone and 44-methylgambierone. Both gambierone and MTX3 induced a small increase in the cytosolic calcium concentration but only MTX3 caused cell cytotoxicity at micromolar concentrations. Moreover, chronic exposure of human cortical neurons to either gambierone or MTX3 altered the expression of ionotropic glutamate receptors, an effect already described before for the synthetic ciguatoxin CTX3C. However, even when gambierone and MTX3 affected glutamate receptor expression in a similar manner their effect on receptor expression differed from that of CTX3C, since both toxins decreased AMPA receptor levels while increasing N-methyl-d-aspartate (NMDA) receptor protein. Thus, further studies should be pursued to clarify the similarities and differences in the biological activity between the known ciguatoxins and the new identified molecule as well as its contribution to the neurological symptoms of ciguatera.
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Project description:Maitotoxins (MTXs) are among the most potent toxins known. These toxins are produced by epi-benthic dinoflagellates of the genera Gambierdiscus and Fukuyoa and may play a role in causing the symptoms associated with Ciguatera Fish Poisoning. A recent survey revealed that, of the species tested, the newly described species from the Canary Islands, G. excentricus, is one of the most maitotoxic. The goal of the present study was to characterize MTX-related compounds produced by this species. Initially, lysates of cells from two Canary Island G. excentricus strains VGO791 and VGO792 were partially purified by (i) liquid-liquid partitioning between dichloromethane and aqueous methanol followed by (ii) size-exclusion chromatography. Fractions from chromatographic separation were screened for MTX toxicity using both the neuroblastoma neuro-2a (N2a) cytotoxicity and Ca2+ flux functional assays. Fractions containing MTX activity were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) to pinpoint potential MTX analogs. Subsequent non-targeted HRMS analysis permitted the identification of a novel MTX analog, maitotoxin-4 (MTX4, accurate mono-isotopic mass of 3292.4860 Da, as free acid form) in the most toxic fractions. HRMS/MS spectra of MTX4 as well as of MTX are presented. In addition, crude methanolic extracts of five other strains of G. excentricus and 37 other strains representing one Fukuyoa species and ten species, one ribotype and one undetermined strain/species of Gambierdiscus were screened for the presence of MTXs using low resolution tandem mass spectrometry (LRMS/MS). This targeted analysis indicated the original maitotoxin (MTX) was only present in one strain (G. australes S080911_1). Putative maitotoxin-2 (p-MTX2) and maitotoxin-3 (p-MTX3) were identified in several other species, but confirmation was not possible because of the lack of reference material. Maitotoxin-4 was detected in all seven strains of G. excentricus examined, independently of their origin (Brazil, Canary Islands and Caribbean), and not detected in any other species. MTX4 may therefore serve as a biomarker for the highly toxic G. excentricus in the Atlantic area.
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Project description:Identifying compounds responsible for the observed toxicity of the Gambierdiscus species is a critical step to ascertaining whether they contribute to ciguatera poisoning. Macroalgae samples were collected during research expeditions to Rarotonga (Cook Islands) and North Meyer Island (Kermadec Islands), from which two new Gambierdiscus species were characterized, G. cheloniae CAWD232 and G. honu CAWD242. Previous chemical and toxicological investigations of these species demonstrated that they did not produce the routinely monitored Pacific ciguatoxins nor maitotoxin-1 (MTX-1), yet were highly toxic to mice via intraperitoneal (i.p.) injection. Bioassay-guided fractionation of methanolic extracts, incorporating wet chemistry and chromatographic techniques, was used to isolate two new MTX analogs; MTX-6 from G. cheloniae CAWD232 and MTX-7 from G. honu CAWD242. Structural characterization of the new MTX analogs used a combination of analytical chemistry techniques, including LC-MS, LC-MS/MS, HR-MS, oxidative cleavage and reduction, and NMR spectroscopy. A substantial portion of the MTX-7 structure was elucidated, and (to a lesser extent) that of MTX-6. Key differences from MTX-1 included monosulfation, additional hydroxyl groups, an extra double bond, and in the case of MTX-7, an additional methyl group. To date, this is the most extensive structural characterization performed on an MTX analog since the complete structure of MTX-1 was published in 1993. MTX-7 was extremely toxic to mice via i.p. injection (LD50 of 0.235 µg/kg), although no toxicity was observed at the highest dose rate via oral administration (155.8 µg/kg). Future research is required to investigate the bioaccumulation and likely biotransformation of the MTX analogs in the marine food web.
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Project description:Understanding the toxicity and production rates of the various secondary metabolites produced by Gambierdiscus and cohabitating benthic dinoflagellates is essential to unravelling the complexities associated with ciguatera poisoning. In the present study, a sulphated cyclic polyether, gambierone, was purified from Gambierdiscus cheloniae CAWD232 and its acute toxicity was determined using intraperitoneal injection into mice. It was shown to be of low toxicity with an LD50 of 2.4 mg/kg, 9600 times less toxic than the commonly implicated Pacific ciguatoxin-1B, indicating it is unlikely to play a role in ciguatera poisoning. In addition, the production of gambierone and 44-methylgambierone was assessed from 20 isolates of ten Gambierdiscus, two Coolia and two Fukuyoa species using quantitative liquid chromatography-tandem mass spectrometry. Gambierone was produced by seven Gambierdiscus species, ranging from 1 to 87 pg/cell, and one species from each of the genera Coolia and Fukuyoa, ranging from 2 to 17 pg/cell. The production of 44-methylgambierone ranged from 5 to 270 pg/cell and was ubiquitous to all Gambierdiscus species tested, as well as both species of Coolia and Fukuyoa. The relative production ratio of these two secondary metabolites revealed that only two species produced more gambierone, G. carpenteri CAWD237 and G. cheloniae CAWD232. This represents the first report of gambierone acute toxicity and production by these cohabitating benthic dinoflagellate species. While these results demonstrate that gambierones are unlikely to pose a risk to human health, further research is required to understand if they bioaccumulate in the marine food web.
| S-EPMC8147941 | biostudies-literature
Project description:Gambierdiscus spp. are epi-benthic dinoflagellates that have been associated with ciguatera poisoning. These microalgae can have complex secondary metabolite profiles including ciguatoxins, maitotoxins, and gambierones, with varying compositions and toxicities across species and strains. Given this chemical diversity there is a need to develop selective and sensitive methods for secondary metabolite profiling. In this study, we used a cultured Caribbean strain of Gambierdiscus silvae to develop sample preparation and analysis strategies for characterizing vic-diol containing secondary metabolites. A pooled cellular extract was first screened by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) for ciguatoxin-related compounds, which resulted in the confirmation of gambierone (1) and a novel isomer of 44-methylgambierone (3). Treatment of the extract with periodate confirmed that the gambierones each contained one reactive vic-diol, which was exploited for the development of a selective extraction procedure using m-aminophenylboronic acid gel and the non-aqueous binding solvent chloroform. Using this non-traditional boronate affinity procedure, LC-HRMS also revealed the presence of additional sulfated polycyclic ethers in the gambierone-containing vic-diol fraction, while pigments and other contaminants were removed. The developed tools could be applied to screen collections of Gambierdiscus and other benthic algae to provide additional chemical characterization of gambierone-related compounds. The selective extraction procedure may also prove useful as a step in the isolation of these sulfated polyethers for structural, toxicological and biotransformation studies.
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Project description:Strigolactones (SLs), carotenoid-derived phytohormones, control the plant response and signaling pathways for stressful conditions. In addition, they impact numerous cellular processes in mammalians and present new scaffolds for various biomedical applications. Recent studies demonstrated that SLs possess potent antitumor activity against several cancer cells. Herein, we sought to elucidate the inhibitory effects of SL analogs on the growth and survival of human brain tumor cell lines. Among four tested SLs, we showed for the first time that two lead bioactiphores, indanone-derived SL and EGO10, can inhibit cancer cell proliferation, induce apoptosis, and induce G1 cell cycle arrest at low concentrations. SL analogs were marked by increased expression of Bax/Caspase-3 genes and downregulation of Bcl-2. In silico studies were conducted to identify drug-likeness, blood-brain barrier penetrating properties, and molecular docking with Bcl-2 protein. Taken together, this study indicates that SLs may be promising antiglioma agents, presenting novel pharmacophores for further preclinical and clinical assessment.
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Project description:A reaction of copper(II) carbonate and potassium 4-sulfo-benzoic acid in water acidified with hydro-chloric acid yielded two crystalline products. Tetra-aqua-bis-(4-carb-oxy-benzene-sulfonato)-copper(II) dihydrate, [Cu(O3SC6H4CO2H)2(H2O)4]·2H2O, (I), crystallizes in the triclinic space group P with the Cu2+ ions located on centers of inversion. Each copper ion is coordinated to four water mol-ecules in a square plane with two sulfonate O atoms in the apical positions of a Jahn-Teller-distorted octa-hedron. The carboxyl-ate group is protonated and not involved in coordination to the metal ions. The complexes pack so as to create a layered structure with alternating inorganic and organic domains. The packing is reinforced by several O-H⋯O hydrogen bonds involving coordinated and non-coordinated water mol-ecules, the carb-oxy-lic acid group and the sulfonate group. Hexa-aqua-copper(II) 4-carb-oxy-benzene-sulfonate, [Cu(H2O)6](O3SC6H4CO2H)2, (II), also crystallizes in the triclinic space group P with Jahn-Teller-distorted octa-hedral copper(II) aqua complexes on the centers of inversion. As in (I), the carboxyl-ate group on the anion is protonated and the structure consists of alternating layers of inorganic cations and organic anions linked by O-H⋯O hydrogen bonds. A reaction of silver nitrate and potassium 4-sulfo-benzoic acid in water also resulted in two distinct products that have been structurally characterized. An anhydrous silver potassium 4-carb-oxy-benzene-sulfonate salt, [Ag0.69K0.31](O3SC6H4CO2H), (III), crystallizes in the monoclinic space group C2/c. There are two independent metal sites, one fully occupied by silver ions and the other showing a 62% K+/38% Ag+ (fixed) ratio, refined in two slightly different positions. The coordination environments of the metal ions are composed primarily of sulfonate O atoms, with some participation by the non-protonated carboxyl-ate O atoms in the disordered site. As in the copper compounds, the cations and anions cleanly segregate into alternating layers. A hydrated mixed silver potassium 4-carb-oxy-benzene-sulfonate salt dihydrate, [Ag0.20K0.80](O3SC6H4CO2H)·2H2O, (IV), crystallizes in the monoclinic space group P21/c with the Ag+ and K+ ions sharing one unique metal site coordinated by two water mol-ecules and six sulfonate O atoms. The packing in (IV) follows the dominant motif of alternating inorganic and organic layers. The protonated carboxyl-ate groups do not inter-act with the cations directly, but do participate in hydrogen bonds with the coordinated water mol-ecules. (IV) is isostructural with pure potassium 4-sulfo-benzoic acid dihydrate.
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Project description:Sulfation is widespread in nature and plays an important role in modulating biological function. Among the strategies developed by microbes to access sulfated oligosaccharides as a nutrient source is the production of 6-sulfoGlcNAcases to selectively release 6-sulfoGlcNAc from target oligosaccharides. Thus far, all 6-sulfoGlcNAcases identified have belonged to the large GH20 family of β-hexosaminidases. Ηere, we identify and characterize a new, highly specific non-GH20 6-sulfoGlcNAcase from Streptococcus pneumoniae TIGR4, Sp_0475 with a greater than 110,000-fold preference toward N-acetyl-β-D-glucosamine-6-sulfate substrates over the nonsulfated version. Sp_0475 shares distant sequence homology with enzymes of GH20 and with the newly formed GH163 family. However, the sequence similarity between them is sufficiently low that Sp_0475 has been assigned as the founding member of a new glycoside hydrolase family, GH185. By combining results from site-directed mutagenesis with mechanistic studies and bioinformatics we provide insight into the substrate specificity, mechanism, and key active site residues of Sp_0475. Enzymes of the GH185 family follow a substrate-assisted mechanism, consistent with their distant homology to the GH20 family, but the catalytic residues involved are quite different. Taken together, our results highlight in more detail how microbes can degrade sulfated oligosaccharides for nutrients.
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Project description:Bacterial communities of cultured Gambierdiscus carolinianus and Gambierdiscus caribaeus Metagenome
| PRJNA594054 | ENA