Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 17, 2026.

Neurotoxic Alkaloids: Saxitoxin and Its Analogs

Maria Wiese, Paul M. D’Agostino, Troco K. Mihali and 2 more

Marine Drugs · 2010 · Review · CC BY

doi:10.3390/md8072185

Abstract

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.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The paralytic shellfish toxins (PSTs) are a group of naturally occurring neurotoxic alkaloids. Saxitoxin (STX) is the most researched PST to date, and since its discovery in 1957, 57 analogs have been described. The PSTs are primarily produced in detrimental concentrations during harmful algal bloom (HAB) events Over the last few decades, HABs have become more frequent, intense, and span a wider global distribution, the cause of which is still under debate. The PSTs can be broadly characterized as hydrophilic or hydrophobic, and can be divided into subgroups based on substituent side chains such as carbamate, sulfate, hydroxyl, hydroxybenzoate, or acetate. Each moiety then imparts a varying level of toxicity.

In marine environments, PSTs are primarily produced by the eukaryotic dinoflagellates, belonging to the genera Alexandrium, Gymnodinium and Pyrodinium. The toxins are passed through the marine food web via vector organisms, which accumulate the toxins by feeding on PST producing dinoflagellates without apparent harm to themselves. These include filter feeding invertebrates such as shellfish, crustaceans, molluscs and also other, non-traditional vectors such as gastropods and planktivorous fish. In freshwater environments the PSTs are produced by prokaryotic cyanobacteria belonging to the genera Anabaena, Cylindrospermopsis, Aphanizomenon, Planktothrix and Lyngbya. Cyanobacterial PST producing blooms result in the contamination of drinking and recreational water resources. In the past, high levels of toxins have been detected in the freshwater resources of many countries such as Australia, Brazil, USA, Mexico, Germany and China.

Intoxication with PSTs may result in the severe and occasionally fatal illness known as paralytic shellfish poisoning (PSP) or saxitoxin pufferfish poisoning (SPFP). This illness is caused when PSTs reversibly bind voltage-gated Na+ channels in an equimolar ratio. This is mediated by the interaction between the positively charged guanidinium groups of STX with negatively charged carboxyl groups at site 1 of the Na+ channel, thereby blocking the pore (Figure 1). Currently, there is no antidote for PSP with artificial respiration and fluid therapy the only treatment available. A recent case of PSP involved the death of two fishermen after consumption of the filter feeder bi-valve Aulacomya ater in the Chilean Patagonian Fjords. The threat of PSP is not only a major cause of concern for public health but is also detrimental to the economy. Outbreaks of PSTs often result in the death of marine life and livestock, the closure of contaminated fisheries, while the continual expenditure required for the maintenance and running of monitoring programs, all combine to present a major economic burden around the world.

This review will focus on the structural diversity of PSTs characterized to date and the biosynthetic and metabolic basis for this diversity. The saxitoxin biosynthetic gene cluster (sxt) was recently identified in cyanobacteria, which now provides insight into the biosynthesis of STX and its analogs. A specific suite of analogs can be isolated from a single PST-producing organism, which is directly a result of the evolution of genes present within the organism’s genome. Naturally occurring PSTs can also be precursors for extracellular metabolic or chemical transformations into new analogs. Knowledge of these transformations may have important implications for the detection, toxicity and removal of PSTs from a contaminated source. Other medicinal uses for PSTs may become more established by screening the bioactivity of less toxic analogs, since their use as a potential local anesthetic has long been known. The characterization of PST biosynthesis genes and their potential use in combinatorial biosynthesis, together with the constant discovery of novel analogs (either natural or transformed), is likely to expand the possibilities for the pharmaceutical use of PSTs.

2. Saxitoxin and Its Analogs, the Paralytic Shellfish Toxins

STX is one of the most potent natural neurotoxins known. A dose of approximately 1 mg of the toxin from a single serving of contaminated shellfish is fatal to humans. STX was the first PST isolated in pure form from the Alaskan butter clam, Saxidomus gigangteus in 1957. Its highly polar characteristics represent poor conditions for crystallization and hampered structure elucidations for 18 years, until the crystal structure was solved by two groups independently in 1975. STX is an alkaloid with the molecular formula C10H17N7O4 (Molecular Weight = 299) and is composed of a 3,4-propinoperhydropurine tricyclic system. STX belongs to the large family of guanidinium-containing marine natural products, due to the presence of two guanidino groups which are responsible for its high polarity. Since its initial discovery, 57 naturally occurring STX analogs have been identified in a number of organisms, collectively referred to as the PSTs (Table 1).

Usually a PST- producing organism synthesizes a characteristic suite of toxins made up of several PST analogs. These analogs differ in side group moieties and thus are commonly grouped according to these variable residues. The most commonly occurring PSTs are hydrophilic and have been studied in depth. They may be non-sulfated, such as STX and neosaxitoxin (neoSTX), mono-sulfated, such as the gonyautoxins (GTXs 1–6), or di-sulfated (C1-4 toxins). In addition, decarbamoyl variants of these analogs also exist, including decarbamoyl-saxitoxins (dcSTX, dcneoSTX), decarbamoyl-gonyautoxins (dcGTXs 1–4), and the 13-deoxy-decarbamoyl derivatives (doSTX, doGTX 2,3). Three structural families of SXT are classified by the identity of the R4 side chain as either N-sulfocarbamoyl, decarbamoyl, or carbamoyl, each with increasing toxicity in mammalian bioassays (Table 2). Recently, an increase in screening efforts, coupled with improved methods for detection and structure elucidation, has seen an increase in the number of new PSTs reported in the literature.

A novel group of PSTs with a hydrophobic side chain were identified within the cyanobacterium Lyngbya wollei and are characterized by the presence of an acetate at C13 (LWTX 1–3,5,6) and a carbinol at C12 (LWTX 2,3,5) in place of a hydrated ketone. This was the first report of STX derivatives with a hydrophobic substituent and these toxins have only been found exclusively in the freshwater environment. The presence of an acetate side chain in the LWTXs correlated with a decrease in mouse toxicity, while the reduction at C12 resulted in a complete loss of mouse toxicity.

Interestingly, Negri et al. reported a novel subclass of analogs containing a hydrophobic R4 side chain designated GC1-3. These were first isolated and structurally characterized from Australian isolates of the dinoflagellate Gymnodinium catenatum and since have also been identified within Alexandrium catenatum globally. High-resolution mass-spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) revealed that GC3 is a 4-hydroxybenzoate ester derivative of dcSTX, while GC1 and GC2 are epimeric 11-hydroxysulfate derivatives of GC3. Negri et al. emphasized that the lipophilic nature of these toxins may lead to an increased potential to bioaccumulate in marine organisms. These novel analogs have also been shown to bind strongly to the voltage gated Na+ channel. The binding affinity of GC3 resembles the affinity of the GTXs, whereas the epimer pair GC1 and GC2 bind with a similar affinity compared to the C-toxins. More recently, other GC PST analogs have been identified, such as GC4-6, the di-hydroxylated benzoate GC analogs GC1-6a and the sulfated benzoate analogs GC1-6b for which only putative structures have been determined via mass spectrometry (MS). Due to their hydrophobic nature, these toxins easily escape conventional chromatography methods. The frequently used C18 solid-phase separation is based on polarity and thus hydrophobic compounds are retained on the column and cannot be detected. This is significant from a shellfish monitoring and public safety viewpoint, and presents a major challenge to water authorities.

Recently, Vale et al. reported the isolation of four unusual compounds (denoted A–D) and categorized them as novel STX analogs based on fluorescence emission, ultraviolet absorption maxima and cross-reactivity to a commercial antibody towards STX. These extracts originated from shellfish samples (Semele proficua and Senilia senilis) collected from Luanda and Mussulo Bay, Angola. Compounds A and D were classified as non-N1-hydroxyl PST analogs and compound B as a N1-hydroxyl analog. Even though the presence of G. catenatum and Pyrodinium bahamense has been reported from the coast of Angola, none of the 18 PSTs commonly found in dinoflagellates were identified in these extracts. The authors therefore suggested a possible cyanobacterial source, though neither a definitive chemical structure, nor a PST-producing organism were conclusively identified. Further analysis of the compounds by MS and NMR is required to elucidate these structures and confirm them as STX analogs.

The most exotic STX isolate identified to date was isolated from the Panamanian golden frog Atelopus zeteki and designated zetekitoxin AB (Tables 1 and 2). Zetekitoxin AB was confirmed to be a PST containing a unique 1,2-oxazolidine ring-fused lactam. The binding affinity of zetekitoxin AB for brain, heart, and muscle Na+ channels was extremely potent, displaying a toxicity of approximately 580-, 160- and 63-fold greater than STX against each channel, respectively.

The constant discovery of novel and diverse STX analogs is a challenge to PST identification and monitoring. Improvement of detection methods will no doubt uncover new natural forms of STX, however, we are still only beginning to understand the mechanisms by which these complex molecules are produced in nature.

3. Biotransformation of the Paralytic Shellfish Toxins

Naturally occurring PSTs may be structurally modified by various biological factors. In some cases, these biotransformations can result in new PSTs that cannot be biosynthesized by cyanobacteria or dinoflagellates alone (Figure 2). In addition, less toxic PSTs may be converted into analogs with greater toxicity (e.g., C-toxins→GTXs) or vice versa. Therefore, a clearer understanding of PST biotransformation is needed for predicting more accurate levels of toxicity. This knowledge may also allow for a mechanism of detoxification to be established and utilized in the water supply and shellfish farming industries.

Cell extracts of PST-producing dinoflagellates are capable of enzymatically modifying PSTs. Oshima et al. demonstrated that GTX2 + 3 can be converted into GTX1 + 4 by incubation with Alexandrium tamarense homogenate. Introduction of a sulfate moiety on the carbamoyl group, resultingin the formation of C1 and C2 toxins, has been shown following incubation with G. catenatum homogenate. In these organisms, biotransformation is likely to occur via inherent STX tailoring enzymes which are a part of the SXT biosynthetic pathway encoded within the organism.

Due to differences in the toxin profiles of filter-feeding invertebrate PST vectors and causative producing organisms, various studies have been conducted to monitor toxin biotransformation. Enzymatic transformation of carbamoyl and carbamoyl-N sulfated toxins into the decarbamoyl compounds was detected within the little neck clam, Prothotheca staminea. In addition, the conversion of the GTXs and neoSTX to STX by reduction of the O22-sulfate and N1-hydroxyl groups, respectively, has been observed within the homogenate of the scallop Placopecten magellanicus.

GC1-3 can be converted into dcSTX, as has been confirmed in vitro through incubation of semi-purified GC toxins with bivalve digestive glands. Similarly, the recently identified M-toxins (M1-5) are reportedly bivalve metabolites of the PSTs and are not present in PST- producing microalgae. The M-toxins constitute an important toxin fraction in mussels contaminated by A. tamarense and G. catenatum and have been detected in shellfish, including mussels, cockles and clams. These findings are similar to previous reports on the isolation of 11-saxitoxinethanoic acid (SEA), a novel PST from the xanthid crab Atergatis floridus, inhabiting the pacific coast of Shikoku Island. Other examples include a novel carbamoyl-N-methylsaxitoxin (STX-uk) isolated from the Bangladeshi freshwater puffer Tetraodon cutcutia. These exotic STX analogs are likely products of toxin transforming enzymes within the vector organism or its associated microorganisms. However, the mechanism of enzymatic transformation in these organisms is yet to be elucidated.

Biotransformation of the PSTs by bacteria was first suggested many years ago by Kotaki et al., who proposed that marine bacteria, such as Vibrio and Pseudomonas spp., are capable of metabolizing PSTs. In addition, isolates from the viscera of marine crabs, snails and the marine red algae Jania sp., were studied and demonstrated transformation GTX derivatives into STX through reductive eliminations. Bacterial conversion of GTX1-4 to STX and neoSTX is reportedly due to the bacterial thiol compounds glutathione and 2-mercaptoethanol. The ability of bacteria to degrade PSTs has been further described by Smith et al., who screened marine bacterial isolates from various shellfish species for their ability to metabolize a range of PSTs, such as GTX1-5, STX and neoSTX, suggesting that bacteria might play an important role in the clearance of PSTs from bivalve molluscs. Novel strains of Pseudoalteromonas haloplanktis, isolated from the digestive tracts of blue mussels (Mytilus edulis) have been reported to possess the ability to reduce the overall toxicity of a PST mixture of algal extracts by 90% within three days. Catabolism of the PSTs most likely occurred via oxidation reactions catalyzed by oxidases and peroxidases into aliphatic products for subsequent use in purine and arginine metabolism, although this is speculated, as no catabolized PST products could be identified. Degradation has also been observed during the passage through a bioactive treatment plant, leading to a decrease in predominant C-toxins and an increase of GTX2 + 3 which display relatively higher toxicity.

Detoxification of the paralytic shellfish toxins within mammals

Metabolism of PSTs by humans has not been studied in depth. Nevertheless, Garcia et al. suggested biotransformation of STX to neoSTX and the oxidation of the GTX2 + 3 epimers into GTX1 + 4 within samples of pancreas, bile, urine, brain and heart obtained post-mortem from PSP victims. Further investigations confirmed their findings of biotransformation in humans. N1-oxidation of GTX2 + 3 into the corresponding hydroxylamine analogs GTX1 + 4 has been demonstrated in vitro when incubated with a microsomal fraction isolated from healthy human livers. Moreover, in vitro glucuronidation of GTX2 + 3 into the hydrophilic compounds GTX3-Gluc and GTX2-Gluc, through conjugation at the hydroxyl-C12 group has also been reported (Figure 2). The oxidation and glucuronidation of STX and GTX2 + 3 epimers into neoSTX or GTX1 + 4 epimers, respectively, has been suggested to be significant detoxification pathways of GTX2 + 3 and other PSTs in humans and other mammals. Similar studies were conducted with cat liver, however, enzymatic transformation was not detected, with 100% recovery of the STX used in the incubation being recovered. This was explained by the fact that with the exception of cats, the liver of mammals produces glucuronides as a major metabolic product, thus supporting the specificity of human tissue transformation. However, biotransformation of STX was not detected when STX was passaged through rat’s urine, indicating further mammalian variability in models. Gessner et al. investigated serum and urine in human PSP victims and detected a significant increase of the PST C1 in comparison to GTX2, which is distinguished by an additional sulfate on the carbamoyl side group. A new assay for STX and neoSTX quantification in human urine samples has been developed recently. It is proposed that methodological improvements should also contribute to a better understanding of PST profile and its change while passaging through the human body.

The research described above highlights the need to characterize the diversity of biological transformations of PSTs. Detoxification pathways could be manipulated to improve biological removal strategies, while further characterization of detoxification of PSTs within the human body could lead to improved treatment of PSP.

4.1. The saxitoxin biosynthetic gene cluster

Recently the saxitoxin biosynthesis pathway was proposed, and the sxt gene cluster was identified in three cyanobacterial species of the family Nostocaceae and one from the family Oscillatoriaceae. The sxt gene clusters within each organism all contain a core set of genes putatively responsible for the biosynthesis of STX. However, the gene profile between each cluster differs, resulting in the production of a different suite of STX analogs by each organism. It is foreseeable that identification of the cyanobacterial PST biosynthesis genes will eventually lead to the identification of the homologs within dinoflagellates. However, the dinoflagellate PST biosynthesis genes remain elusive. There is also some debate on whether the enzymes for PST biosynthesis are encoded by the dinoflagellate genome, including plastids or other sources such as symbiotic bacteria or viruses.

In cyanobacteria, biosynthesis of STX is catalyzed by several enzymes otherwise rare in microbial metabolism. The core PST biosynthetic gene, sxtA, is thought to have a chimeric origin and is putatively responsible for the initiation of STX biosynthesis, catalysing the incorporation of acetate to the enzyme complex and its subsequent methylation and Claisen condensation with arginine. SxtA consists of four catalytic domains (SxtA1-SxtA4) with the N-terminal region showing similarities to a polyketide synthase (PKS) complex consisting of a GCN5-related N-acetyltransferase, acyl-carrier protein (ACP) and a S-adenosylmethionine-dependant (SAM) methyltransferase domains, while the C-terminal region contains a domain homologous to previously characterized aminotransferases.

Specific PST analog profiles are proposed to be the result of tailoring enzymes encoded by the sxt gene cluster. The function of tailoring enzymes within each of the characterized sxt clusters has been inferred by analysis of the specific toxin profile produced by each cyanobacterium. For example, neoSTX differs from STX by hydroxylation at the N1 position (Table 1). NeoSTX is produced by C. raciborskii T3, Aphanizomenon sp. NH-5 and L. wollei, but has not been detected in A. circinalis. Sequence analysis of the four sxt gene clusters revealed SxtX as a protein putatively responsible for the N1-hydroxylation of STX, since sxtX was identified in all neoSTX producing strains and absent from the A. circinalis AWQC131C gene cluster. This protein displayed high structural similarities to cephalosporin hydroxylase, further affirming its role in the N1-hydroxylation of STX.

The GTXs are produced by mono-sulfation at N21 or O22 of STX which can then be di-sulfated to produce the C-toxins. Previous studies of the dinoflagellate G. catenatum, revealed two 3′-phosphate 5′-phosphosulfate (PAPS)-dependant sulfotransferases responsible for the N21 sulfation of STX, GTX2 and GTX3, and the O22 sulfation of 11-hydroxy STX. Two genes, sxtO, a PAPS forming enzyme and sxtN, a sulfotransferase, within cyanobacterial sxt clusters are proposed to encode proteins that play a similar sulfation role in the synthesis of GTXs and C-toxins.

The requirement of SAM for STX biosynthesis has long been hypothesized and thus has been targeted during attempts to identify the PST genes. Harlow et al. were able to use degenerate primers to screen several dinoflagellate genomes in an attempt to identify genes encoding SAM as a candidate involved in PST biosynthesis. Although several SAM genes were successfully identified within dinoflagellates, these were not correlated to PST biosynthesis. The study was hampered by a limited knowledge of dinoflagellate codon usage and a lack of related sequence information within the NCBI database. Kellmann et al. used a similar degenerate PCR approach to identify a gene encoding a O-carbamoyltransferase (sxtI), which ultimately led to the identification of the entire sxt biosynthesis pathway in cyanobacteria. There are now multiple genes that may be utilized to target homologs of the sxt cluster in dinoflagellates. However, a recent study identified the dinoflagellate sxt cluster may differ from cyanobacteria more than would be expected from a recent gene transfer event. Hence, mRNA present solely within toxic dinoflagellates may be more successful at identifying the candidate sxt pathway in these organisms.

4.2. Pharmaceutical potential of the paralytic shellfish toxins

Recent years has seen a renewed interest in marine alkaloids and their analogs, including the PSTs, with regards to their use as therapeutic agents or as a drug lead. Bioactivity studies and molecular modeling of a range of PSTs could also lead to the design of unnatural analogs with improved pharmaceutical characteristics. Recently, a group of toxins isolated from marine cone snails (genus Conus), known as conotoxins, have been shown to contain over 2,000 peptide analogs. The conotoxins are able to specifically target a broad range of ion channels and membrane receptors with several currently under investigation for possible clinical trials. In 2004, a synthetic version of a single conotoxin analog, ω-conotoxin MVIIA, also known as ziconotide (trade name Prialt®) was the first marine natural product to be approved for use by the US Food and Drug Administration since 1976. Ziconotide acts by targeting N-type voltage sensitive Ca2+ channels and is used for the treatment of chronic pain in spinal cord injury.

Like Prialt®, STX also has a huge pharmaceutical potential for its ability to induce anesthesia through interaction with site 1 of the voltage gated Na+ channel. It has been suggested that site 1 blockers prolong the duration of anaesthesia in a synergistic manner when combined with other local anaesthetics. In spite of this, the push for STX to enter clinical trials has been hindered by its systematic toxicity. The use of STX as a slow release, prolonged anesthetic was recently demonstrated using a novel controlled release system in male Sprague-Dawley rats. Liposomal formulations of STX, either alone and in conjunction with dexamethasone and/or bupivacaine, were able to block the sciatic nerve within rats for long periods with no damaging myotoxic, cytotoxic or neurotoxic effects and little associated inflammation. Liposome formulations of STX for slow and site-directed release for prolonged anaesthesia have since been postulated as a putative treatment of localized pain and severe joint pain.

PSTs such as GTX2 + 3 also have clinical potential and have been utilized for the treatment of anal fissures. Since 1951, surgery has been the most common form of anal fissure treatment with several possible side effects, while other treatments include ointments, botulinium toxin and topical application of nitroglycerine. Treatment with GTX2 + 3 involves direct injection into both sides of the fissure. A success rate of 98% with remission after 15 and 28 days for acute and chronic conditions, respectively (n = 100) was observed. A follow up study with an enhanced method has since been performed by Garrido et al. with an improved time of healing of seven to 14 days for chronic cases (n = 23). Both studies identified GTX2 + 3 as safe and effective when compared to other treatments. GTX2 + 3 have also been used in the treatment of chronic tension type headache, with 70% of patients (n = 27) responding to treatment. These studies recognize that PSTs other than STX also have potential as future pharmaceutical leads. Their use in the past has also been limited largely due to problems obtaining purified PST analogs.

The genetic characterization of PST biosynthesis pathways from diverse producer organisms has increased our insight into sxt tailoring reactions and the molecular understanding of the mechanisms by which a particular suite of PSTs can be synthesized. This will ultimately advance research into the pharmaceutical potential of the PSTs as Na+ channel blockers, by generating new analogs or by increasing the availability of analogs otherwise biosynthesized in low concentrations. Bioengineering can also be utilized to further enhance the structural diversity of bioactive small molecules by using in vitro approaches that utilize enzymes in chemical synthesis, as well as in vivo approaches, such as combinatorial biosynthesis. Combinatorial biosynthesis is the process of incorporating genes from multiple biosynthetic clusters into an expression plasmid, in a combinatorial fashion, to generate a library of “unnatural” natural products expressed in vivo. However expression of large gene fragments in a heterologous host is required and analogs of interest may then be extracted, purified and assayed to determine their bioactivity.

The bioactive nature of STX as an anaesthetic and GTX2 + 3 for the treatment of anal fissures and chronic tension type headaches demonstrates that these alkaloids have pharmaceutical potential deserving of further investigation. The recent elucidation of the sxt gene clusters in cyanobacteria and the identification of novel PSTs has provided more options for further PST bioactivity studies. Novel analogs could also be devised by redesigning PST biosynthesis genes in amenable host systems via combinatorial biosynthesis.

5. Conclusions

The structure of STX has been known for 53 years and the discovery of novel STX analogs has continued steadily ever since. Today, 57 PST analogs have been reported. With more sensitive detection methods, new STX analogs will most likely continue to be identified, with new functional moieties and possibly novel bioactivity. Despite extended research on the role of saxitoxin and its analogs as a sodium channel blocker, the effect of these toxins on the environment, and the genes that are responsible for their production, there is still a vast gap in knowledge in regards to their potential intracellular role within the producing organism. Nevertheless, it is possible that the different analogs display varying functions within the cells due to their partial differences in charges and chemical properties. More studies are needed to elucidate the localization of saxitoxin and its derivatives might provide clues to the potential role of the PST analogs within the producing organism. In the future, a better understanding of the intracellular and extracellular functions of STX might open more avenues for pharmaceutical applications.

Since PSTs are produced by distantly related organisms, spanning two domains, including cyanobacteria, dinoflagellates and the Panamanian golden frog, it is possible that their occurrence in nature is more widespread than we know. Further investigations are needed to elucidate the extent of their distribution, diversity and their fundamental biology, such as their biosynthesis, metabolic and eco-physiological function. This is in addition to the role of chemical transformation of the different toxins in shellfish and the environment.

Future research is also needed to understand the integration of PST biosynthesis within the overall cell metabolism and the possible recruitment of enzymes from other biosynthetic pathways for PST bioconversions. Proteomic and transcriptomic studies are likely to provide a link between STX biosynthesis, regulation and cellular metabolism. It is expected that data will allow us to acquire a better understanding of the conservation of the SXT biosynthesis pathway at the enzymatic level in comparison to the genetic level, may give further insight into the molecular function of these toxins and also lead to clues of their evolutionary history. In future, characterization of PST biosynthetic genes from dinoflagellates and comparison with cyanobacterial genes will also aid in our understanding of the evolutionary history of these genes with regard to their origin and transfer.

PSP is a serious health problem and its incidence has continued to rise on a global scale. PSTs negatively impact the fisheries industry globally and the development of novel methods of detoxification is essential from a human health and financial perspective. The enzymatic basis for the structural diversity of PSTs is now beginning to be understood from the genetics of their biosynthesis in cyanobacteria and characterization of transformations catalyzed by bacteria, marine invertebrates and mammals. Biotransformation pathways could also be manipulated to efficiently remove toxins from water supplies. Specific enzymes or bacterial strains that degrade PSTs could be introduced into shellfish to assist detoxification. Currently, the PSTs represent extraordinary potential for pharmacy. This potential is likely to increase as we continue to gain a better molecular understanding of the PSTs, leading to future prospects of their use in combinatorial biosynthesis for the production of novel alkaloids with beneficial application.

References 162

  1. 1.

    Schantz EJ Mold J Stanger D Shavel J Riel F Bowden J Lynch J Wyler R Riegel B Sommer H Paralytic shellfish poison VI. A procedure for the isolation and purification of the poison from toxic clams and mussel tissuesJ. Am. Chem. Soc1957 7952305235

    Not in our library

  2. 2.

    Anderson DM Cembella AD Hallegraeff GM Physiological Ecology of Harmful Algal Blooms1st edSpringerBerlin, Germany1998 662

    Not in our library

  3. 3.

    Anderson DM Glibert PM Burkholder JM Harmful algal blooms and eutrophication: Nutrient sources, composition, and consequencesEstuaries2002 25704726

    Not in our library

  4. 4.

    Sellner KG Doucette GJ Kirkpatrick GJ Harmful algal blooms: Causes, impacts and detectionJ. Ind. Microbiol. Biotechnol2003 30383406

    Not in our library10.1007/s10295-003-0074-9

  5. 5.

    Zingone A Enevoldsen HO The diversity of harmful algal blooms: A challenge for science and managementOcean Coast. Manage2000 43725748

    Not in our library

  6. 6.
    Marine algal toxins: origins, health effects, and their increased occurrence. · 2000
    No notice
  7. 7.

    Llewellyn LE Saxitoxin, a toxic marine natural product that targets a multitude of receptorsNat. Prod. Rep2006 23200222

    Not in our library10.1039/b501296c

  8. 8.

    Lefebvre KA Bill BD Erickson A Baugh KA O'Rourke L Costa PR Nance S Trainer VL Characterization of intracellular and extracellular saxitoxin levels in both field and cultured Alexandrium spp. samples from Sequim Bay, WashingtonMar. Drugs2008 6103116

    Not in our library10.3390/md20080006

  9. 9.

    Oshima Y Blackburn SI Hallegraeff GM Comparative study on paralytic shellfish toxin profiles of the dinoflagellate Gymnodinium catenatum from three different countriesMar. Biol1993 116471476

    Not in our library

  10. 10.

    Usup G Kulis DM Anderson DM Growth and toxin production of the toxic dinoflagellate Pyrodinium bahamense var. compressum in laboratory culturesNat. Toxins1994 2254262

    Not in our library10.1002/nt.2620020503

  11. 11.

    Gainey L Shumway J Shumway S A compendium of the responses of bivalve molluscs to toxic dinoflagellatesJ. Shellfish Res1988 7623628

    Not in our library

  12. 12.

    Shumway SE Phycotoxin-related shellfish poisoning: Bivalve molluscs are not the only vectorsRev. Fish. Sci1995 3131

    Not in our library

  13. 13.
    Non-Traditional Vectors for Paralytic Shellfish Poisoning · 2008
    No notice
  14. 14.

    Carmichael WW Evans WR Yin QQ Bell P Moczydlowski E Evidence for paralytic shellfish poisons in the freshwater cyanobacterium Lyngbya wollei (Farlow ex Gomont) comb. novAppl. Environ. Microbiol1997 6331043110

    Not in our library10.1128/aem.63.8.3104-3110.1997

  15. 15.

    Hoeger SJ Shaw G Hitzfeld BC Dietrich DR Occurrence and elimination of cyanobacterial toxins in two Australian drinking water treatment plantsToxicon2004 43639649

    Not in our library10.1016/j.toxicon.2004.02.019

  16. 16.

    Molica RJR Oliveira EJA Carvalho PVVC Costa ANSF Cunha MCC Melo GL Azevedo SMFO Occurrence of saxitoxins and an anatoxin-a(s)-like anticholinesterase in a Brazilian drinking water supplyHarmful Algae2005 4743753

    Not in our library

  17. 17.

    Clemente Z Busato RH Oliveira Ribeiro CA Cestari MM Ramsdorf WA Magalhães VF Wosiack AC Silva de Assis HC Analyses of paralytic shellfish toxins and biomarkers in a southern Brazilian reservoirToxicon2010 55396406

    Not in our library10.1016/j.toxicon.2009.09.003

  18. 18.

    Liu Y Chen W Li D Shen Y Li G Liu Y First report of aphantoxins in China—waterblooms of toxigenic Aphanizomenon flos-aquae in Lake DianchiEcotoxicol. Environ. Saf2006 658492

    Not in our library10.1016/j.ecoenv.2005.06.012

  19. 19.

    Berry JP Lind O First evidence of "paralytic shellfish toxins" and cylindrospermopsin in a Mexican freshwater system, Lago Catemaco, and apparent bioaccumulation of the toxins in "tegogolo" snails (Pomacea patula catemacensis)Toxicon2010 55930938

    Not in our library10.1016/j.toxicon.2009.07.035

  20. 20.

    Ballot A Fastner J Wiedner C Paralytic shellfish poisoning toxin-producing cyanobacterium Aphanizomenon gracile in Northeast GermanyAppl. Environ. Microbiol2010 7611731180

    Not in our library10.1128/aem.02285-09

  21. 21.

    Codd GA Cyanobacterial toxins: occurrence, properties and biological significanceWater Sci. Technol1995 32149156

    Not in our library

  22. 22.

    Sivonen K Jones G Chorus I Bartram J Cyanobacterial toxinsToxin Cyanobacteria in Water: A Guide to Their Public Health Consequences, Monitoring and ManagementWHO E & FN SponLondon, UK1999 41111

    Not in our library

  23. 23.

    Kao CY Falconer ER Paralytic shellfish poisoningAlgal Toxins in Seafood and Drinking WaterAcademicLondon, UK1993 75

    Not in our library

  24. 24.

    Anderson DM Kulis DM Qi Y Zheng L Lu S Lin Y Paralytic shellfish poisoning in Southern ChinaToxicon1996 34579590

    Not in our library10.1016/0041-0101(95)00158-1

  25. 25.

    Rodrigue DC Etzel RA Hall S de Porras E Velasquez OH Tauxe RV Kilbourne EM Blake PA Lethal paralytic shellfish poisoning in GuatemalaAm. J. Trop. Med. Hyg1990 42267271

    Not in our library10.4269/ajtmh.1990.42.267

  26. 26.

    Garcia C del Carmen Bravo M Lagos M Lagos N Paralytic shellfish poisoning: Post-mortem analysis of tissue and body fluid samples from human victims in the Patagonia fjordsToxicon2004 43149158

    Not in our library10.1016/j.toxicon.2003.11.018

  27. 27.

    Landsberg JH Hall S Johannessen JN White KD Conrad SM Abbott JP Flewelling LJ Richardson RW Dickey RW Jester EL Etheridge SM Deeds JR Van Dolah FM Leighfield TA Zou Y Beaudry CG Benner RA Rogers PL Scott PS Kawabata K Wolny JL Steidinger KA Saxitoxin puffer fish poisoning in the United States, with the first report of Pyrodinium bahamense as the putative toxin sourceEnviron. Health Perspect2006 11415021507

    Not in our library10.1289/ehp.8998

  28. 28.

    Catterall WA Morrow CS Hartshorne RP Neurotoxin binding to receptor sites associated with voltage-sensitive sodium channels in intact, lysed, and detergent-solubilized brain membranesJ. Biol. Chem1979 2541137911387

    Not in our library

  29. 29.

    Catterall WA Neurotoxins that act on voltage-sensitive sodium channels in excitable membranesAnnu. Rev. Pharmacol1980 201543

    Not in our library10.1146/annurev.pa.20.040180.000311

  30. 30.

    Cestèle S Catterall WA Molecular mechanisms of neurotoxin action on voltage-gated sodium channelsBiochimie2000 82883892

    Not in our library10.1016/s0300-9084(00)01174-3

  31. 31.

    Guy AL Griffin G Adopting alternatives for the regulatory monitoring of shellfish for paralytic shellfish poisoning in Canada: Interface between federal regulators, science and ethicsRegul. Toxicol. Pharmacol2009 54256263

    Not in our library10.1016/j.yrtph.2009.05.002

  32. 32.

    Stewart I Seawright AA Shaw GR Hudnell HK Cyanobacterial poisoning in livestock, wild mammals and birds—an overviewCyanobacterial Harmful Algal Blooms: State of the Science and Research NeedsSpringerNew York, NY, USA2008 613637

    Not in our library10.1007/978-0-387-75865-7_28

  33. 33.

    Kellmann R Mihali TK Jeon YJ Pickford R Pomati F Neilan BA Biosynthetic intermediate analysis and functional homology reveal a saxitoxin gene cluster in cyanobacteriaAppl. Environ. Microbiol2008 7440444053

    Not in our library10.1128/aem.00353-08

  34. 34.
    Characterisation of the paralytic shellfish toxin biosynthesis gene clusters in Anabaena circinalis AWQC131C and Aphanizomenon sp. NH-5 · 2009
    No notice
  35. 35.

    Llewellyn LE Negri AP Doyle J Baker PD Beltran EC Neilan BA Radioreceptor assays for sensitive detection and quantitation of saxitoxin and its analogues from strains of the freshwater cyanobacterium, Anabaena circinalisEnviron. Sci. Technol2001 3514451451

    Not in our library10.1021/es001575z

  36. 36.

    Lagos N Onodera H Zagatto PA Andrinolo D Azevedo SMFQ Oshima Y The first evidence of paralytic shellfish toxins in the freshwater cyanobacterium Cylindrospermopsis raciborskii, isolated from BrazilToxicon1999 3713591373

    Not in our library10.1016/s0041-0101(99)00080-x

  37. 37.

    Ferreira FMB Soler JMF Fidalgo ML Fernández-Vila P PSP toxins from Aphanizomenon flos-aquae (cyanobacteria) collected in the Crestuma-Lever reservoir (Douro river, northern Portugal)Toxicon2001 39757761

    Not in our library10.1016/s0041-0101(00)00114-8

  38. 38.

    Hille B The receptor for tetrodotoxin and saxitoxin. A structural hypothesisBiophys. J1975 15615619

    Not in our library10.1016/s0006-3495(75)85842-5

  39. 39.

    Adams HJ Blair MR Jr Takman BH The local anesthetic activity of saxitoxin alone and with vasoconstrictor and local anesthetic agentsArch. Int. Pharmacodyn. Ther1976 224275282

    Not in our library

  40. 40.

    Khosla C Keasling JD Metabolic engineering for drug discovery and developmentNat. Rev. Drug Discov2003 210191025

    Not in our library10.1038/nrd1256

  41. 41.

    Zhang W Tang Y Combinatorial biosynthesis of natural productsJ. Med. Chem2008 5126292633

    Not in our library10.1021/jm701269v

  42. 42.

    Bordner J Thiessen WE Bates HA Rapoport H Structure of a crystalline derivative of saxitoxin. Structure of saxitoxinJ. Am. Chem. Soc1975 9760086012

    Not in our library10.1021/ja00854a009

  43. 43.

    Schantz EJ Ghazarossian VE Schnoes HK Strong FM Springer JP Pezzanite JO Clardy J Structure of saxitoxinJ. Am. Chem. Soc1975 9712381239

    Not in our library10.1021/ja00838a045

  44. 44.

    Shimizu Y Botana LM Chemistry and mechanism of actionSeafood and Freshwater Toxins: Pharmacology, Physiology, and DetectionMarcel DekkerNew York, NY, USA2000 151172

    Not in our library

  45. 45.

    Berlinck RGS Kossuga MH Natural guanidine derivativesNat. Prod. Rep2005 22516550

    Not in our library10.1039/b209227c

  46. 46.

    Ciminiello P Fattorusso E Forino M Montresor M Saxitoxin and neosaxitoxin as toxic principles of Alexandrium andersoni (Dinophyceae) from the Gulf of Naples, ItalyToxicon2000 3818711877

    Not in our library10.1016/s0041-0101(00)00099-4

  47. 47.

    Siu G Young M Chan D Environmental and nutritional factors which regulate population dynamics and toxin production in the dinoflagellate Alexandrium catenellaHydrobiologia1997 352117140

    Not in our library

  48. 48.

    Sebastián CR Etheridge SM Cook PA O'Ryan C Pitcher GC Phylogenetic analysis of toxic Alexandrium (Dinophyceae) isolates from South Africa: implications for the global phylogeography of the Alexandrium tamarense species complexPhycologia2005 444960

    Not in our library

  49. 49.

    Krock B Seguel CG Cembella AD Toxin profile of Alexandrium catenella from the Chilean coast as determined by liquid chromatography with fluorescence detection and liquid chromatography coupled with tandem mass spectrometryHarmful Algae2007 6734744

    Not in our library

  50. 50.

    Poulton NJ Keafer BA Anderson DM Toxin variability in natural populations of Alexandrium fundyense in Casco Bay, Maine—evidence of nitrogen limitationDeep-Sea Res. PT. II2005 5225012521

    Not in our library

  51. 51.

    Anderson DM Kulis DM Sullivan JJ Hall S Toxin composition variations in one isolate of the dinoflagellate Alexandrium fundyenseToxicon1990 28885893

    Not in our library10.1016/0041-0101(90)90018-3

  52. 52.

    Jaime E Gerdts G Luckas B In vitro transformation of PSP toxins by different shellfish tissuesHarmful Algae2007 6308316

    Not in our library

  53. 53.

    Parkhill J Cembella A Effects of salinity, light and inorganic nitrogen on growth and toxigenicity of the marine dinoflagellate Alexandrium tamarense from northeastern CanadaJ. Plankton Res1999 21939955

    Not in our library

  54. 54.

    Yu R Hummert C Luckas B Qian P Li J Zhou M A modified HPLC method for analysis of PSP toxins in algae and shellfish from chinaChromatographia1998 48671676

    Not in our library

  55. 55.

    Ichimi K Suzuki T Ito A Variety of PSP toxin profiles in various culture strains of Alexandrium tamarense and change of toxin profile in natural A. tamarense populationJ. Exp. Mar. Biol. Ecol2002 2735160

    Not in our library

  56. 56.

    Dell'Aversano C Walter JA Burton IW Stirling DJ Fattorusso E Quilliam MA Isolation and structure elucidation of new and unusual saxitoxin analogues from musselsJ. Nat. Prod2008 7115181523

    Not in our library10.1021/np800066r

  57. 57.

    Velzeboer RMA Baker PD Rositano J Heresztyn T Codd GA Raggett SL Geographical patterns of occurrence and composition of saxitoxins in the cyanobacterial genus Anabaena (Nostocales, Cyanophyta) in AustraliaPhycologia2000 39395407

    Not in our library

  58. 58.

    Testé V Briand J-F Nicholson BC Puiseux-Dao S Comparison of changes in toxicity during growth of Anabaena circinalis (cyanobacteria) determined by mouse neuroblastoma bioassay and HPLCJ. Appl. Phycol2002 14399407

    Not in our library

  59. 59.

    Negri AP Jones GJ Bioaccumulation of paralytic shellfish poisoning (PSP) toxins from the cyanobacterium Anabaena circinalis by the freshwater mussel Alathyria condolaToxicon1995 33667678

    Not in our library10.1016/0041-0101(94)00180-g

  60. 60.

    Dias E Pereira P Franca S Production of the paralytic shellfish toxins by Aphanizomenon sp. LMECYA 31 (cyanobacteria)J. Phycol2002 38705712

    Not in our library

  61. 61.

    Ikawa M Wegener K Foxall TL Sasner JJ Jr Comparison of the toxins of the blue-green alga Aphanizomenon flos-aquae with the Gonyaulax toxinsToxicon1982 20747752

    Not in our library10.1016/0041-0101(82)90122-2

  62. 62.

    Mahmood NA Carmichael WW Paralytic shellfish poisons produced by the freshwater cyanobacterium Aphanizomenon flos-aquae NH-5Toxicon1986 24175186

    Not in our library10.1016/0041-0101(86)90120-0

  63. 63.

    Pereira P Onodera H Andrinolo D Franca S Araújo F Lagos N Oshima Y Paralytic shellfish toxins in the freshwater cyanobacterium Aphanizomenon flos-aquae, isolated from Montargil reservoir, PortugalToxicon2000 3816891702

    Not in our library10.1016/s0041-0101(00)00100-8

  64. 64.

    Pereira P Li R Carmichael W Dias E Franca S Taxonomy and production of paralytic shellfish toxins by the freshwater cyanobacterium Aphanizomenon gracile LMECYA40Eur. J. Phycol2004 39361368

    Not in our library

  65. 65.

    Nogueira ICG Pereira P Dias E Pflugmacher S Wiegand C Franca S Vasconcelos VM Accumulation of paralytic shellfish toxins (PST) from the cyanobacterium Aphanizomenon issatschenkoi by the cladoceran Daphnia magnaToxicon2004 44773780

    Not in our library10.1016/j.toxicon.2004.08.006

  66. 66.

    Rapala J Robertson A Negri AP Berg KA Tuomi P Lyra C Erkomaa K Lahti K Hoppu K Lepistö L First report of saxitoxin in Finnish lakes and possible associated effects on human healthEnviron. Toxicol2005 20331340

    Not in our library10.1002/tox.20109

  67. 67.

    Castro D Vera D Lagos N García C Vásquez M The effect of temperature on growth and production of paralytic shellfish poisoning toxins by the cyanobacterium Cylindrospermopsis raciborskii C10Toxicon2004 44483489

    Not in our library10.1016/j.toxicon.2004.06.005

  68. 68.

    Pomati F Moffitt MC Cavaliere R Neilan BA Evidence for differences in the metabolism of saxitoxin and C1+2 toxins in the freshwater cyanobacterium Cylindrospermopsis raciborskii T3BBA-Gen. Subjects2004 16746067

    Not in our library10.1016/j.bbagen.2004.05.006

  69. 69.

    Molica R Onodbra H Garcia C Rivas M Andrinolo D Nascimento S Meguro H Oshimo Y Azevedo S Lagos N Toxins in the freshwater cyanobacterium Cylindrospermopsis raciborskii (Cyanophyceae) isolated from Tabocas reservoir in Caruaru, Brazil, including demonstration of a new saxitoxin analoguePhycologia2002 41606611

    Not in our library

  70. 70.

    Holmes MJ Bolch CJS Green DH Cembella AD Teo SLM Singapore isolates of the dinoflagellate Gymnodinium catenatum (Dinophyceae) produce a unique profile of paralytic shellfish poisoning toxinsJ. Phycol2002 3896106

    Not in our library

  71. 71.

    Gárate-Lizárraga I Bustillos-Guzmán JJ Morquecho L Band-Schmidt CJ Alonso-Rodríguez R Erler K Luckas B Reyes-Salinas A Góngora-González DT Comparative paralytic shellfish toxin profiles in the strains of Gymnodinium catenatum Graham from the Gulf of California, MexicoMar. Pollut. Bull2005 50211217

    Not in our library10.1016/j.marpolbul.2004.11.034

  72. 72.

    Negri AP Bolch CJS Geier S Green DH Park T-G Blackburn SI Widespread presence of hydrophobic paralytic shellfish toxins in Gymnodinium catenatumHarmful Algae2007 6774780

    Not in our library

  73. 73.

    Pomati F Sacchi S Rossetti C Giovannardi S Onodera H Oshima Y Neilan BA The freshwater cyanobacterium Planktothrix sp. FP1: Molecular identification and detection of paralytic shellfish poisoning toxinsJ. Phycol2000 36553562

    Not in our library10.1046/j.1529-8817.2000.99181.x

  74. 74.

    Liu Y Chen W Li D Shen Y Liu Y Song L Analysis of paralytic shellfish toxins in Aphanizomenon DC-1 from Lake Dianchi, ChinaEnviron. Toxicol2006 21289295

    Not in our library10.1002/tox.20182

  75. 75.

    Navarro JM Muñoz MG Contreras AM Temperature as a factor regulating growth and toxin content in the dinoflagellate Alexandrium catenellaHarmful Algae2006 5762769

    Not in our library

  76. 76.

    Samsur M Yamaguchi Y Sagara T Takatani T Arakawa O Noguchi T Accumulation and depuration profiles of PSP toxins in the short-necked clam Tapes japonica fed with the toxic dinoflagellate Alexandrium catenellaToxicon2006 48323330

    Not in our library10.1016/j.toxicon.2006.06.002

  77. 77.

    Franco J Fernández P Reguera B Toxin profiles of natural populations and cultures of Alexandrium minutum Halim from Galician (Spain) coastal watersJ. Appl. Phycol1994 6275279

    Not in our library

  78. 78.

    Hwang D-F Lu Y-H Noguchi T Effects of exogenous polyamines on growth, toxicity, and toxin profile of dinoflagellate Alexandrium minutumJ. Food Hyg. Soc. Jpn2003 444953

    Not in our library10.3358/shokueishi.44.49

  79. 79.

    Pitcher GC Cembella AD Joyce LB Larsen J Probyn TA Ruiz Sebastián C The dinoflagellate Alexandrium minutum in Cape Town harbour (South Africa): Bloom characteristics, phylogenetic analysis and toxin compositionHarmful Algae2007 6823836

    Not in our library

  80. 80.

    Hansen PJ Cembella AD Moestrup Ø The marine dinoflagellate Alexandrium ostenfeldii: Paralytic shellfish toxin concentration, composition and toxicity to a tintinnid cilliateJ. Phycol1992 28597603

    Not in our library

  81. 81.

    Vale P Metabolites of saxitoxin analogues in bivalves contaminated by Gymnodinium catenatumToxicon2010 55162165

    Not in our library10.1016/j.toxicon.2009.07.010

  82. 82.

    Onodera H Satake M Oshima Y Yasumoto T Carmichael WW New saxitoxin analogues from the freshwater filamentous cyanobacterium Lyngbya wolleiNat. Toxins1997 5146151

    Not in our library10.1002/1522-7189(1997)5:4<146::aid-nt4>3.0.co;2-v

  83. 83.

    Negri A Stirling D Quilliam M Blackburn S Bolch C Burton I Eaglesham G Thomas K Walter J Willis R Three novel hydroxybenzoate saxitoxin analogues isolated from the dinoflagellate Gymnodinium catenatumChem. Res. Toxicol2003 1610291033

    Not in our library10.1021/tx034037j

  84. 84.

    Oshima Y Sugino K Itakura H Hirota M Yasumoto T Grane'li E Sundstrom B Edler L Anderson DM Comparative studies on paralytic shellfish toxin profile of dinoflagellates and bivalvesToxic Marine PhytoplanktonElsevier Science PublishingNew York, NY, USA1990 391396

    Not in our library

  85. 85.

    Vale P Complex profiles of hydrophobic paralytic shellfish poisoning compounds in Gymnodinium catenatum identified by liquid chromatography with fluorescence detection and mass spectrometryJ. Chromatogr. A2008 11958593

    Not in our library10.1016/j.chroma.2008.04.073

  86. 86.

    Vale P Rangel I Silva B Coelho P Vilar A Atypical profiles of paralytic shellfish poisoning toxins in shellfish from Luanda and Mussulo bays, AngolaToxicon2009 53176183

    Not in our library10.1016/j.toxicon.2008.10.029

  87. 87.

    Arakawa O Nishio S Noguchi T Shida Y Onoue Y A new saxitoxin analogue from a xanthid crab Atergatis floridusToxicon1995 3315771584

    Not in our library10.1016/0041-0101(95)00106-9

  88. 88.

    Zaman L Arakawa O Shimosu A Shida Y Onoue Y Occurrence of a methyl derivative of saxitoxin in Bangladeshi freshwater puffersToxicon1998 36627630

    Not in our library10.1016/s0041-0101(97)00086-x

  89. 89.

    Yotsu-Yamashita M Kim YH Dudley SC Choudhary G Pfahnl A Oshima Y Daly JW The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: A potent sodium-channel blockerProc. Natl. Acad. Sci. USA2004 10143464351

    Not in our library10.1073/pnas.0400368101

  90. 90.

    van Apeldoorn ME van Egmond HP Speijers GJA Bakker GJI Toxins of cyanobacteriaMol. Nutr. Food Res2007 51760

    Not in our library10.1002/mnfr.200600185

  91. 91.

    Negri AP Bolch CJ Blackbum SI Dickman M Llewellyn LE Mendez S Hallegraeff G Bolch CJ Blackburn SI Lewis RJ Paralytic shellfish toxins in Gymnodinium catenatum strains from six countriesHarmfull Algal Blooms 2000Intergovernmental Oceanographic Commission of UNESCOParis, France2001 210213

    Not in our library

  92. 92.

    Llewellyn L Negri A Quilliam M High affinity for the rat brain sodium channel of newly discovered hydroxybenzoate saxitoxin analogues from the dinoflagellate Gymnodinium catenatumToxicon2004 43101104

    Not in our library10.1016/j.toxicon.2003.10.016

  93. 93.

    Vale P Fate of benzoate paralytic shellfish poisoning toxins from Gymnodinium catenatum in shellfish and fish detected by pre-column oxidation and liquid chromatography with fluorescence detectionJ. Chromatogr. A2008 1190191197

    Not in our library10.1016/j.chroma.2008.03.009

  94. 94.

    Codd GA Morrison LF Metcalf JS Cyanobacterial toxins: risk management for health protectionToxicol. Appl. Pharm2005 203264272

    Not in our library10.1016/j.taap.2004.02.016

  95. 95.

    Usleber E Donald M Straka M Märtlbauer E Comparison of enzyme immunoassay and mouse bioassay for determining paralytic shellfish poisoning toxins in shellfishFood Addit. Contam1997 14193198

    Not in our library10.1080/02652039709374514

  96. 96.

    Genenah AA Shimizu Y Specific toxicity of paralytic shellfish poisonsJ. Agr. Food Chem1981 2912891291

    Not in our library10.1021/jf00108a047

  97. 97.

    Sullivan JJ Wekell MM Kentala LL Application of HPLC for the Determination of PSP Toxins in ShellfishJ. Food Sci1985 502629

    Not in our library

  98. 98.

    Oshima Y Sugino K Yasumoto T Mycotoxins and Phycotoxins '88Elsevier Applied ScienceAmsterdam, The Netherlands1989

    Not in our library

  99. 99.

    Oshima Y Lassus P Arzul G Erard E Gentien P Marcaillou C Chemical and enzymatic transformation of paralytic shellfish toxins in marine organismsHarmful Marine Algal BloomsLavoisierParis, France1995

    Not in our library

  100. 100.

    Asakawa M Miyazawa K Takayama H Noguchi T Dinoflagellate Alexandrium tamarense as the source of paralytic shellfish poison (PSP) contained in bivalves from Hiroshima Bay, Hiroshima Prefecture, JapanToxicon1995 33691697

    Not in our library10.1016/0041-0101(94)00177-a

  101. 101.

    Bricelj VM Lee JH Cembella AD Influence of dinoflagellate cell toxicity on uptake and loss of paralytic shellfish toxins in the northern quahog Mercenaria mercenariaMar. Ecol. Prog. Ser1991 743346

    Not in our library

  102. 102.

    Bricelj VM Lee JH Cembella AD Anderson DM Uptake kinetics of paralytic shellfish toxins from the dinoflagellate Alexandrium fundyense in the mussel Mytilus edulisMar. Ecol. Prog. Ser1990 63177188

    Not in our library

  103. 103.

    Cembella AD Shumway SE Lewis NI Anatomical distribution and spatio-temporal variation in paralytic shellfish toxin composition in two bivalve species from the Gulf of MaineJ. Shellfish Res1993 12389403

    Not in our library

  104. 104.

    Lassus P Bardouill M Massselin P Naviner P Truquet P Comparative efficiencies of different non-toxic microalgal diets in detoxification of PSP-contaminated oysters (Crassoatrea gigas Thunberg)J. Nat. Toxins2000 9112

    Not in our library

  105. 105.

    Oshima Y Fallon WE Shimizu Y Noguchi T Hashimoto Y Toxins of the Gonyaulax sp. and infested bivalves in Owase BayBull. Jpn. Soc. Sci. Fish1976 42851856

    Not in our library

  106. 106.

    Sullivan JJ Iwaoka WT Liston J Enzymatic transformation of PSP toxins in the littleneck clam (Protothaca staminea)Biochem. Biophys. Res. Commun1983 114465472

    Not in our library10.1016/0006-291x(83)90803-3

  107. 107.

    Shimizu Y Yoshioka M Transformation of paralytic shellfish toxins as demonstrated in scallop homogenatesScience1981 212547549

    Not in our library10.1126/science.7209548

  108. 108.

    Lu Y Hwang D Effects of toxic dinoflagellates and toxin biotransformation in bivalvesJ. Nat. Toxins2002 11315322

    Not in our library

  109. 109.

    Fast MD Cembella AD Ross NW In vitro transformation of paralytic shellfish toxins in the clams Mya arenaria and Protothaca stamineaHarmful Algae2006 57990

    Not in our library

  110. 110.

    Kotaki Y Oshima Y Yasumoto T Bacterial transformation of paralytic shellfish toxins in coral reef crabs and a marine snailNippon Suisan Gakk1985 5110091013

    Not in our library

  111. 111.

    Kotaki Y Screening of bacteria which convert gonyautoxin 2,3 to saxitoxinNippon Suisan Gakk1989 551293

    Not in our library

  112. 112.

    Sugawara A Imamura T Aso S Ebitani K Change of paralytic shellfish poison by the marine bacteria living in the intestine of the Japanese surf clam, Pseudocardium sybillae, and the brown sole, Pleuronectes herensteiniSci. Rep. Hokkaido Fish. Exp. Stat1997 503542

    Not in our library

  113. 113.

    Smith EA Grant F Ferguson CMJ Gallacher S Biotransformations of paralytic shellfish toxins by bacteria isolated from bivalve molluscsAppl. Environ. Microbiol2001 6723452353

    Not in our library10.1128/aem.67.5.2345-2353.2001

  114. 114.

    Donovan CJ Garduno RA Kalmokoff M Ku JC Quilliam MA Gill TA Pseudoalteromonas bacteria are capable of degrading paralytic shellfish toxinsAppl. Environ. Microbiol2009 7569196923

    Not in our library10.1128/aem.01384-09

  115. 115.

    Donovan CJ Ku JC Quilliam MA Gill TA Bacterial degradation of paralytic shellfish toxinsToxicon2008 5291100

    Not in our library10.1016/j.toxicon.2008.05.005

  116. 116.

    Kayal N Newcombe G Ho L Investigating the fate of saxitoxins in biologically active water treatment plant filtersEnviron. Toxicol2008 23751755

    Not in our library10.1002/tox.20384

  117. 117.

    García C Rodriguez-Navarro A Díaz JC Torres R Lagos N Evidence of in vitro glucuronidation and enzymatic transformation of paralytic shellfish toxins by healthy human liver microsomes fractionToxicon2009 53206213

    Not in our library10.1016/j.toxicon.2008.10.028

  118. 118.

    Andrinolo D Michea LF Lagos N Toxic effects, pharmacokinetics and clearance of saxitoxin, a component of paralytic shellfish poison (PSP), in catsToxicon1999 37447464

    Not in our library10.1016/s0041-0101(98)00173-1

  119. 119.

    Kasper BC Henton D Jakob WB GlucuronidationEnzymatic Basis of DetoxicationAcademicNew York, NY, USA1960 1

    Not in our library

  120. 120.

    Stafford RG Hines HB Urinary elimination of saxitoxin after intravenous injectionToxicon1995 3315011510

    Not in our library10.1016/0041-0101(95)00081-v

  121. 121.

    Hines H Naseem S Wannemacher RJ 3H-Saxitoxinol metabolism and elimination in the ratToxicon1993 31905908

    Not in our library10.1016/0041-0101(93)90226-9

  122. 122.

    Gessner BD Bell P Doucette GJ Moczydlowski E Poli MA Van Dolah F Hall S Hypertension and identification of toxin in human urine and serum following a cluster of mussel-associated paralytic shellfish poisoning outbreaksToxicon1997 35711722

    Not in our library10.1016/s0041-0101(96)00154-7

  123. 123.

    Johnson RC Zhou Y Statler K Thomas J Cox F Hall S Barr JR Quantification of saxitoxin and neosaxitoxin in human urine utilizing isotope dilution tandem mass spectrometryJ. Anal. Toxicol2009 33814

    Not in our library10.1093/jat/33.1.8

  124. 124.

    Kellmann R Neilan BA Biochemical characterization of paralytic shellfish toxin biosynthesis in vitroJ. Phycol2007 43497508

    Not in our library

  125. 125.

    Mihali TK Carmichael WW Neilan BA Biosynthesis of the Lyngbya wollei (Farlow ex Gomont) paralytic shellfish toxins - natural biocombinatoricsPLoS One2010 Submitted for publication

    Not in our library10.1371/journal.pone.0014657

  126. 126.

    Prol MJ Guisande C Barreiro A Miguez B de la Iglesia P Villar A Gago-Martinez A Combarro MP Evaluation of the production of paralytic shellfish poisoning toxins by extracellular bacteria isolated from the toxic dinoflagellate Alexandrium minutumCan. J. Microbiol2009 55943954

    Not in our library10.1139/w09-047

  127. 127.

    Baker TR Doucette GJ Powell CL Boyer GL Plumley FG GTX4 imposters: Characterization of fluorescent compounds synthesized by Pseudomonas stutzeri SF/PS and Pseudomonas/Alteromonas PTB-1, symbionts of saxitoxin-producing Alexandrium sppToxicon2003 41339347

    Not in our library10.1016/s0041-0101(02)00314-8

  128. 128.

    Gallacher S Flynn K Franco J Brueggemann E Hines H Evidence for production of paralytic shellfish toxins by bacteria associated with Alexandrium spp. (Dinophyta) in cultureAppl. Environ. Microbiol1997 63239245

    Not in our library10.1128/aem.63.1.239-245.1997

  129. 129.

    Moustafa A Loram JE Hackett JD Anderson DM Plumley FG Bhattacharya D Origin of saxitoxin biosynthetic genes in cyanobacteriaPLoS ONE2009 4e5758

    Not in our library10.1371/journal.pone.0005758

  130. 130.

    Hill AM The biosynthesis, molecular genetics and enzymology of the polyketide-derived metabolitesNat. Prod. Rep2006 23256320

    Not in our library10.1039/b301028g

  131. 131.

    Wolf E Vassilev A Makino Y Sali A Nakatani Y Burley SK Crystal Structure of a GCN5-Related N-acetyltransferase: Serratia marcescens Aminoglycoside 3-N-acetyltransferaseCell1998 94439449

    Not in our library10.1016/s0092-8674(00)81585-8

  132. 132.

    Kagan RM Clarke S Widespread occurrence of three sequence motifs in diverse S-adenosylmethionine-dependent methyltransferases suggests a common structure for these enzymesArch. Biochem. Biophys1994 310417427

    Not in our library10.1006/abbi.1994.1187

  133. 133.

    Alexander FW Sandmeier E Mehta PK Christen P Evolutionary relationships among pyridoxal-5′-phosphate-dependent enzymesEur. J. Biochem1994 219953960

    Not in our library10.1111/j.1432-1033.1994.tb18577.x

  134. 134.

    Alexander DC Jensen SE Investigation of the Streptomyces clavuligerus cephamycin C gene cluster and its regulation by the CcaR proteinJ. Bacteriol1998 18040684079

    Not in our library10.1128/jb.180.16.4068-4079.1998

  135. 135.

    Yoshida T Sako Y Uchida A Kakutani T Arakawa O Noguchi T Ishida Y Purification and characterization of sulfotransferase specific to O-22 of 11-hydroxy saxitoxin from the toxic dinoflagellate Gymnodinium catenatum (dinophyceae)Fish. Sci2002 68634642

    Not in our library

  136. 136.

    Sako Y Yoshida T Uchida A Arakawa O Noguchi T Ishida Y Purification and characterization of a sulfotransferase specific to N-21 of saxitoxin and gonyautosin 2+3 from the toxic dinoflagellate Gymnodinium catenatum (Dinophyceae)J. Phycol2001 3710441051

    Not in our library

  137. 137.

    Shimizu Y Microalgal metabolitesChem. Rev1993 9316851698

    Not in our library

  138. 138.

    Harlow LD Koutoulis A Hallegraeff GM S-adenosylmethionine synthetase genes from eleven marine dinoflagellatesPhycologia2007 464653

    Not in our library

  139. 139.

    Altschul SF Madden TL Schaffer AA Zhang J Zhang Z Miller W Lipman DJ Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Res1997 2533893402

    Not in our library10.1093/nar/25.17.3389

  140. 140.

    Kellmann R Mihali TK Neilan BA Identification of a saxitoxin biosynthesis gene with a history of frequent horizontal gene transfersJ. Mol. Evol2008 67526538

    Not in our library10.1007/s00239-008-9169-2

  141. 141.

    Yang I John U Beszteri S Glockner G Krock B Goesmann A Cembella A Comparative gene expression in toxic versus non-toxic strains of the marine dinoflagellate Alexandrium minutumBMC Genomics2010 11248

    Not in our library10.1186/1471-2164-11-248

  142. 142.

    Halai R Craik DJ Conotoxins: Natural product drug leadsNat. Prod. Rep2009 26526536

    Not in our library10.1039/b819311h

  143. 143.

    Klotz U Ziconotide—a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain—a short reviewInt. J. Clin. Pharmacol. Ther2006 44478483

    Not in our library10.5414/cpp44478

  144. 144.

    Glaser KB Mayer AMS A renaissance in marine pharmacology: From preclinical curiosity to clinical realityBiochem. Pharmacol2009 78440448

    Not in our library10.1016/j.bcp.2009.04.015

  145. 145.

    Olivera BM Cruz LJ de Santos V LeCheminant GW Griffin D Zeikus R McIntosh M Galyean R Varga J Gray WR Rivier J Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venomBiochemistry1987 2620862090

    Not in our library10.1021/bi00382a004

  146. 146.

    Molinski TF Dalisay DS Lievens SL Saludes JP Drug development from marine natural productsNat. Rev. Drug Discov2009 86985

    Not in our library10.1038/nrd2487

  147. 147.

    Kohane DS Yieh J Lu NT Langer R Strichartz GR Berde CB A re-examination of tetrodotoxin for prolonged duration local anesthesiaAnesthesiology1998 89119131

    Not in our library10.1097/00000542-199807000-00019

  148. 148.

    Barnet CS Tse JY Kohane DS Site 1 sodium channel blockers prolong the duration of sciatic nerve blockade from tricyclic antidepressantsPain2004 110432438

    Not in our library10.1016/j.pain.2004.04.027

  149. 149.

    Kohane DS Lu NT Gökgöl-Kline AC Shubina M Kuang Y Hall S Strichartz GR Berde CB The local anesthetic properties and toxicity of saxitonin homologues for rat sciatic nerve block in vivoReg. Anesth. Pain Med2000 255259

    Not in our library10.1016/s1098-7339(00)80011-5

  150. 150.

    Epstein-Barash H Shichor I Kwon AH Hall S Lawlor MW Langer R Kohane DS Prolonged duration local anesthesia with minimal toxicityProc. Natl. Acad. Sci. USA2009 10671257130

    Not in our library10.1073/pnas.0900598106

  151. 151.

    Chorny M Levy RJ Site-specific analgesia with sustained release liposomesProc. Natl. Acad. Sci. USA2009 10668916892

    Not in our library10.1073/pnas.0903079106

  152. 152.

    Garrido R Lagos N Lattes K Azolas CG Bocic G Cuneo A Chiong H Jensen C Henriquez AI Fernandez C The gonyautoxin 2/3 epimers reduces anal tone when injected in the anal sphincter of healthy adultsBiol. Res2004 37395403

    Not in our library10.4067/s0716-97602004000300005

  153. 153.

    Garrido R Lagos N Lattes K Abedrapo M Bocic G Cuneo A Chiong H Jensen C Azolas R Henriquez A Garcia C Gonyautoxin: New treatment for healing acute and chronic anal fissuresDis. Colon Rectum2005 48335343

    Not in our library10.1007/s10350-004-0893-4

  154. 154.

    Garrido R Lagos N Lagos M Rodríguez-Navarro AJ Garcia C Truan D Henriquez A Treatment of chronic anal fissure by gonyautoxinColorectal Dis2007 9619624

    Not in our library10.1111/j.1463-1318.2006.01183.x

  155. 155.

    Eisenhammer S The surgical correction of chronic internal anal (sphincteric) contractureS. Afr. Med. J1951 25486489

    Not in our library

  156. 156.

    Khubchandani IT Reed JF Sequelae of internal sphincterotomy for chronic fissure in anoBr. J. Surg1989 76431434

    Not in our library10.1002/bjs.1800760504

  157. 157.

    Hsu T-C MacKeigan J Surgical treatment of chronic anal fissureDis. Colon Rectum1984 27475478

    Not in our library10.1007/bf02555546

  158. 158.

    Ezri T Susmallian S Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissureDis. Colon Rectum2003 46805808

    Not in our library10.1007/s10350-004-6660-8

  159. 159.

    Maria G Brisinda G Bentivoglio AR Cassetta E Gui D Albanese A Botulinum toxin injections in the internal anal sphincter for the treatment of chronic anal fissure: Long-term results after two different dosage regimensAnn. Surg1998 228664669

    Not in our library10.1097/00000658-199811000-00005

  160. 160.

    Gorfine SR Topical nitroglycerin therapy for anal fissures and ulcersN. Engl. J. Med1995 33311561157

    Not in our library10.1056/nejm199510263331718

  161. 161.

    Lattes K Venegas P Lagos N Lagos M Pedraza L Rodriguez-Navarro AJ Garcia C Local infiltration of gonyautoxin is safe and effective in treatment of chronic tension-type headacheNeurol. Res2009 31228233

    Not in our library10.1179/174313209x380829

  162. 162.

    Yan T Fu M Li J Yu R Zhou M Accumulation, transformation and elimination of PSP in Mytilus edulisOceanol. Limnol. Sin2001 32421427

    Not in our library

Cited by papers we hold 4

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.