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Angewandte Chemie (International Ed. in... Jun 2014The paralytic agent (+)-saxitoxin (STX), most commonly associated with oceanic red tides and shellfish poisoning, is a potent inhibitor of electrical conduction in... (Review)
Review
The paralytic agent (+)-saxitoxin (STX), most commonly associated with oceanic red tides and shellfish poisoning, is a potent inhibitor of electrical conduction in cells. Its nefarious effects result from inhibition of voltage-gated sodium channels (Na(V)s), the obligatory proteins responsible for the initiation and propagation of action potentials. In the annals of ion channel research, the identification and characterization of Na(V)s trace to the availability of STX and an allied guanidinium derivative, tetrodotoxin. The mystique of STX is expressed in both its function and form, as this uniquely compact dication boasts more heteroatoms than carbon centers. This Review highlights both the chemistry and chemical biology of this fascinating natural product, and offers a perspective as to how molecular design and synthesis may be used to explore Na(V) structure and function.
Topics: Biological Products; Saxitoxin; Sodium Channels
PubMed: 24771635
DOI: 10.1002/anie.201308235 -
Marine Drugs Feb 2020Saxitoxin is an alkaloid neurotoxin originally isolated from the clam in 1957. This group of neurotoxins is produced by several species of freshwater cyanobacteria and... (Review)
Review
Saxitoxin is an alkaloid neurotoxin originally isolated from the clam in 1957. This group of neurotoxins is produced by several species of freshwater cyanobacteria and marine dinoflagellates. The saxitoxin biosynthesis pathway was described for the first time in the 1980s and, since then, it was studied in more than seven cyanobacterial genera, comprising 26 genes that form a cluster ranging from 25.7 kb to 35 kb in sequence length. Due to the complexity of the genomic landscape, saxitoxin biosynthesis in dinoflagellates remains unknown. In order to reveal and understand the dynamics of the activity in such impressive unicellular organisms with a complex genome, a strategy that can carefully engage them in a systems view is necessary. Advances in omics technology (the collective tools of biological sciences) facilitated high-throughput studies of the genome, transcriptome, proteome, and metabolome of dinoflagellates. The omics approach was utilized to address saxitoxin-producing dinoflagellates in response to environmental stresses to improve understanding of dinoflagellates gene-environment interactions. Therefore, in this review, the progress in understanding dinoflagellate saxitoxin biosynthesis using an omics approach is emphasized. Further potential applications of metabolomics and genomics to unravel novel insights into saxitoxin biosynthesis in dinoflagellates are also reviewed.
Topics: Biosynthetic Pathways; Cyanobacteria; Dinoflagellida; Genomics; Metabolomics; Neurotoxins; Protein Biosynthesis; Proteomics; Saxitoxin; Transcriptome
PubMed: 32033403
DOI: 10.3390/md18020103 -
Marine Drugs Aug 2013Numerous species of marine dinoflagellates synthesize the potent environmental neurotoxic alkaloid, saxitoxin, the agent of the human illness, paralytic shellfish... (Review)
Review
Numerous species of marine dinoflagellates synthesize the potent environmental neurotoxic alkaloid, saxitoxin, the agent of the human illness, paralytic shellfish poisoning. In addition, certain freshwater species of cyanobacteria also synthesize the same toxic compound, with the biosynthetic pathway and genes responsible being recently reported. Three theories have been postulated to explain the origin of saxitoxin in dinoflagellates: The production of saxitoxin by co-cultured bacteria rather than the dinoflagellates themselves, convergent evolution within both dinoflagellates and bacteria and horizontal gene transfer between dinoflagellates and bacteria. The discovery of cyanobacterial saxitoxin homologs in dinoflagellates has enabled us for the first time to evaluate these theories. Here, we review the distribution of saxitoxin within the dinoflagellates and our knowledge of its genetic basis to determine the likely evolutionary origins of this potent neurotoxin.
Topics: Animals; Cyanobacteria; Dinoflagellida; Gene Transfer, Horizontal; Humans; Neurotoxins; Saxitoxin; Shellfish Poisoning
PubMed: 23966031
DOI: 10.3390/md11082814 -
Natural Product Reports Apr 2006Saxitoxin (STX) was discovered early last century and can contaminate seafood and drinking water, and over time has become an invaluable research tool and an... (Review)
Review
Saxitoxin (STX) was discovered early last century and can contaminate seafood and drinking water, and over time has become an invaluable research tool and an internationally regulated chemical weapon. Among natural products, toxins obtain a unique reputation from their high affinity and selectivity for their target pharmacological receptor, which for STX has long been considered to only be the voltage gated sodium channel. In recent times however, STX has been discovered to also bind to calcium and potassium channels, neuronal nitric oxide synthase, STX metabolizing enzymes and two circulatory fluid proteins, namely a transferrin-like family of proteins and a unique protein found in the blood of pufferfish.
Topics: Amino Acid Sequence; Animals; Biological Products; Chemical Warfare Agents; Fishes; Food Contamination; Ion Channels; Marine Toxins; Molecular Sequence Data; Molecular Structure; Receptors, Cell Surface; Saxitoxin
PubMed: 16572228
DOI: 10.1039/b501296c -
Marine Drugs Jul 2010Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative... (Review)
Review
Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs--each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids.
Topics: Alkaloids; Animals; Humans; Marine Toxins; Neurotoxins; Saxitoxin; Shellfish Poisoning
PubMed: 20714432
DOI: 10.3390/md8072185 -
Mini Reviews in Medicinal Chemistry 2017Tetrodotoxin (TTX) found in diverse variety of animals including puffer fishes, some newts, frogs and limited number of non-vertebrate species (6 different phyla). The... (Review)
Review
Tetrodotoxin (TTX) found in diverse variety of animals including puffer fishes, some newts, frogs and limited number of non-vertebrate species (6 different phyla). The saxitoxin (STX) and the TTX are small molecules composed of 7,8,9 guanidinium and 1,2,3 guanidinium groups, respectively in their structures. These groups provide positive charge to the molecules and are believed to interact with negatively charged Glu755 and Asp400 residues in domain II and I of the sodium channel strongly. The pharmacokinetic studies (absorption, distribution and accumulation) reported on Takifugu rubripes, Takifugu pardalis, Takifugu niphobles, Takifugu vermicularis, Takifugu snyderi, etc. revealed that higher concentration of TTX is accumulated in liver than in the skin or other tissues. Although TTX is also accumulated in the skin of various marine species (secretory glands) and the excess of TTX are emitted through skin which acts as a defence agent for those species. STX showed high toxicity on crab and other animals, due to its accumulation in the tissues and resistance to the sodium channel proteins. It concluded that TTX and STX based toxicities are developed on the species by the absorption, distribution and accumulation of toxins in tissues. Also the ingestion of these species (marine species) as food may allow transferring toxin to the human being.
Topics: Animals; Binding Sites; Humans; Saxitoxin; Sodium Channel Blockers; Sodium Channels; Takifugu; Tetrodotoxin
PubMed: 27306745
DOI: No ID Found -
Toxins Dec 2023Marine pufferfish, which naturally possess tetrodotoxins (TTXs), selectively take up and accumulate TTXs, whereas freshwater pufferfish, which naturally possess...
Marine pufferfish, which naturally possess tetrodotoxins (TTXs), selectively take up and accumulate TTXs, whereas freshwater pufferfish, which naturally possess saxitoxins (STXs), selectively take up and accumulate STXs. To further clarify the TTXs/STXs selectivity in pufferfish, we conducted a TTX/STX administration experiment using , a euryhaline marine pufferfish possessing both TTXs and STXs. Forty nontoxic cultured individuals of were divided into a seawater group (SW, acclimated/reared at 33‱ salinity; = 20) and a brackish water group (BW, acclimated/reared at 8‱ salinity; = 20). An aqueous TTX/STX mixture was intrarectally administered (both at 7.5 nmol/fish), and five individuals/group were analyzed after 1-48 h. Instrumental toxin analyses revealed that both TTX and STX were taken up, transferred, and retained, but more STX than TTX was retained in both groups. TTX gradually decreased and eventually became almost undetectable in the intestinal tissue, while STX was retained at ~5-10% of the dose level, and only STX showed transient transfer in the liver. The BW group showed a faster decrease/disappearance of TTX, greater STX retention in the intestine, and greater STX transient transfer to the liver. Thus, appears to more easily accumulate STXs than TTXs, especially under hypoosmotic conditions.
Topics: Animals; Saxitoxin; Tetrodotoxin; Takifugu; Fresh Water; Liver
PubMed: 38251235
DOI: 10.3390/toxins16010018 -
Environmental Toxicology and... Dec 2016Saxitoxin (STX) and its analogs, the paralytic shellfish toxins (PSTs), are a group of potent neurotoxins well known for their role in acute paralytic poisoning by... (Review)
Review
Saxitoxin (STX) and its analogs, the paralytic shellfish toxins (PSTs), are a group of potent neurotoxins well known for their role in acute paralytic poisoning by preventing the generation of action potentials in neuronal cells. They are found in both marine and freshwater environments globally and although acute exposure from the former has previously received more attention, low dose extended exposure from both sources is possible and to date has not been investigated. Given the known role of cellular electrical activity in neurodevelopment this pattern of exposure may be a significant public health concern. Additionally, the presence of PSTs is likely to be an ongoing and possibly increasing problem in the future. This review examines the neurodevelopmental toxicity of STX, the risk of extended or repeated exposure to doses with neurodevelopmental effects, the potential implications of this exposure and briefly, the steps taken and difficulties faced in preventing exposure.
Topics: Animals; Climate Change; Cyanobacteria; Dinoflagellida; Dose-Response Relationship, Drug; Environmental Exposure; Fresh Water; Humans; Ion Channels; Molecular Structure; Neurotoxicity Syndromes; Saxitoxin; Seawater; Shellfish Poisoning; Time Factors; Water Pollutants, Chemical
PubMed: 27716534
DOI: 10.1016/j.etap.2016.09.020 -
Toxins Oct 2019Paralytic shellfish poisoning (PSP) is precipitated by a family of toxins produced by harmful algae, which are consumed by filter-feeding and commercially popular...
Paralytic shellfish poisoning (PSP) is precipitated by a family of toxins produced by harmful algae, which are consumed by filter-feeding and commercially popular shellfish. The toxins, including saxitoxin, neosaxitoxin, and gonyautoxins, accumulate in shellfish and cause intoxication when consumed by humans and animals. Symptoms can range from minor neurological dysfunction to respiratory distress and death. There are over 40 different chemical congeners of saxitoxin and its analogs, many of which are toxic and many of which have low toxicity or are non-toxic. This makes accurate toxicity assessment difficult and complicates decisions regarding whether or not shellfish are safe to consume. In this study, we describe a new antibody-based bioassay that is able to detect toxic congeners (saxitoxin, neosaxitoxin, and gonyautoxins) with little cross-reactivity with the low or non-toxic congeners (decarbamoylated or di-sulfated forms). The anti-saxitoxin antibody used in this assay detects saxitoxin and neosaxitoxin, the two most toxic congers equally well, but not the relatively highly toxic gonyautoxins. By incorporating an incubation step with L-cysteine, it is possible to convert a majority of the gonyautoxins present to saxitoxin and neosaxitoxin, which are readily detected. The assay is, therefore, capable of detecting the most toxic PSP congeners found in commercially relevant shellfish. The assay was validated against samples whose toxicity was determined using standard HPLC methods and yielded a strong linear agreement between the methods, with R2 values of 0.94-0.96. As ELISAs are rapid, inexpensive, and easy-to-use, this new commercially available PSP ELISA represents an advance in technology allowing better safety management of the seafood supply and the ability to screen large numbers of samples that can occur when monitoring is increased substantially in response to toxic bloom events.
Topics: Data Accuracy; Enzyme-Linked Immunosorbent Assay; Food Contamination; Marine Toxins; Saxitoxin; Shellfish Poisoning
PubMed: 31683507
DOI: 10.3390/toxins11110632 -
Marine Drugs Mar 2013Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium,... (Review)
Review
Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types. This review provides a summary of marine neurotoxins, including their structures, molecular targets and pharmacologies. Saxitoxin and its derivatives, collectively referred to as paralytic shellfish toxins (PSTs), are unique among neurotoxins in that they are found in both marine and freshwater environments by organisms inhabiting two kingdoms of life. Prokaryotic cyanobacteria are responsible for PST production in freshwater systems, while eukaryotic dinoflagellates are the main producers in marine waters. Bioaccumulation by filter-feeding bivalves and fish and subsequent transfer through the food web results in the potentially fatal human illnesses, paralytic shellfish poisoning and saxitoxin pufferfish poisoning. These illnesses are a result of saxitoxin's ability to bind to the voltage-gated sodium channel, blocking the passage of nerve impulses and leading to death via respiratory paralysis. Recent advances in saxitoxin research are discussed, including the molecular biology of toxin synthesis, new protein targets, association with metal-binding motifs and methods of detection. The eco-evolutionary role(s) PSTs may serve for phytoplankton species that produce them are also discussed.
Topics: Animals; Calcium Channels; Humans; Marine Toxins; Potassium Channels, Voltage-Gated; Saxitoxin; Shellfish Poisoning; Voltage-Gated Sodium Channels
PubMed: 23535394
DOI: 10.3390/md11040991