Saxitoxin Blocks L-TypeICa

Su, Zhi; Sheets, Michael F.; Ishida, Hideyuki; Li, Fenghua; Barry, William H.

doi:10.1124/jpet.103.056564

Cited by 124 publications

(72 citation statements)

References 25 publications

(29 reference statements)

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“…These toxins block voltage-gated sodium and calcium channels and prolong the gating of potassium channels (21,53,59), preventing the transduction of neuronal signals. It has been estimated that more than 2,000 human cases of PSP occur globally every year at a mortality rate of 15% (16).…”

mentioning

confidence: 99%

Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria

Kellmann

Mihali

Jeon

et al. 2008

Appl Environ Microbiol

322

444

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Saxitoxin (STX) and its analogues cause the paralytic shellfish poisoning (PSP) syndrome, which afflicts human health and impacts coastal shellfish economies worldwide. PSP toxins are unique alkaloids, being produced by both prokaryotes and eukaryotes. Here we describe a candidate PSP toxin biosynthesis gene cluster (sxt) from Cylindrospermopsis raciborskii T3. The saxitoxin biosynthetic pathway is encoded by more than 35 kb, and comparative sequence analysis assigns 30 catalytic functions to 26 proteins. STX biosynthesis is initiated with arginine, S-adenosylmethionine, and acetate by a new type of polyketide synthase, which can putatively perform a methylation of acetate, and a Claisen condensation reaction between propionate and arginine. Further steps involve enzymes catalyzing three heterocyclizations and various tailoring reactions that result in the numerous isoforms of saxitoxin. In the absence of a gene transfer system in these microorganisms, we have revised the description of the known STX biosynthetic pathway, with in silico functional inferences based on sxt open reading frames combined with liquid chromatography-tandem mass spectrometry analysis of the biosynthetic intermediates. Our results indicate the evolutionary origin for the production of PSP toxins in an ancestral cyanobacterium with genetic contributions from diverse phylogenetic lineages of bacteria and provide a quantum addition to the catalytic collective available for future combinatorial biosyntheses. The distribution of these genes also supports the idea of the involvement of this gene cluster in STX production in various cyanobacteria.Paralytic shellfish poisoning (PSP) toxins are among the world's most potent and pervasive toxins and are considered a serious toxicological health risk that may affect humans, animals, and ecosystems worldwide (18,36). These toxins block voltage-gated sodium and calcium channels and prolong the gating of potassium channels (21, 53, 59), preventing the transduction of neuronal signals. It has been estimated that more than 2,000 human cases of PSP occur globally every year at a mortality rate of 15% (16). Moreover, coastal blooms of productive microorganisms result in millions of dollars of economic damage due to PSP toxin contamination of seafood and the continuous requirement for costly biotoxin monitoring programs. Early warning systems to anticipate the occurrence of paralytic shellfish toxin (PST)-producing algal blooms, such as PCR and enzyme-linked immunosorbent assay-based screening, are as yet unavailable due to the lack of data on the genetic basis of PST production.Saxitoxin (STX) is a tricyclic perhydropurine alkaloid that can be substituted at various positions, leading to more than 30 naturally occurring STX analogues (4,5,28,32,33,63). Although STX biosynthesis seems complex and unique, organisms from two kingdoms, including certain species of marine dinoflagellates and freshwater cyanobacteria, are capable of producing these toxins, apparently by the same biosynthetic route (47). In spit...

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mentioning

confidence: 99%

Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria

Kellmann

Mihali

Jeon

et al. 2008

Appl Environ Microbiol

322

444

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“…PSTs affect vertebrate nerve function by reversibly blocking voltage-gated ion channels, primarily Na + (Llewellyn, 2006), but also K + and Ca 2+ channels are affected (Kao, 1986, Wang et al, 2003, Su et al, 2004. Ion channel blockage leads to inhibition of neuronal signal transduction, the extent of which is directly dependent on PST concentration.…”

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confidence: 99%

First report of cyanobacterial paralytic shellfish toxin biosynthesis genes and paralytic shellfish toxin production in Polish freshwater lakes

et al. 2017

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In central and southern Europe, Aphanizomenon spp., A. gracile Lemmermann in particular, have been associated with paralytic shellfish toxin (PST) production. In western Poland, A. gracile is very common, and Cylindrospermopsis raciborskii (Woloszyńska) Seenayya & Subba Raju, another potentially PST-producing species, is often found as well. To date it is, however, unknown if the cyanobacterial populations in this area harbour the genetic capability to produce PSTs, and to what extent toxin biosynthesis occurs. The objective of this study was to survey the prevalence of potentially PST-producing cyanobacteria by measuring paralytic shellfish toxin biosynthesis gene sxtB copy numbers, sxtA, sxtG and sxtS gene presence, and PST concentrations in Polish freshwater lakes. In total, 34 lakes in western Poland were sampled twice during summer 2010. The presence of PST biosynthesis genes sxtA, sxtG and sxtS was determined using conventional qualitative PCR. Quantitative PCR (qPCR) was used to measure sxtB copy numbers, and the samples were analysed for PSTs using ion-pair high performance liquid chromatography with post-column oxidation and fluorescence detection (HPLC-FLD). Cyanobacteria carrying the sxtB gene were present in 23.5% of all samples (n=16) and in 14 lakes of the studied 34. Gene copy numbers ranged from 8.2×104 to 5.1×107 sxtB copies L-1 (mean 3.8×106). The median was 4.5×105 sxtB gene copies L-1 and the majority of results clustered at the lower end of the sxtB qPCR linear range. In 12 out of the 16 samples positive for sxtB the gene co-occurred with the other three targeted PST biosynthesis genes sxtA, sxtG and sxtS. However, five additional samples lacked one or two of the targeted four genes. Thirteen samples contained PSTs, of which 12 samples at levels <0.072 µg L-1, i.e., close to or below the quantitative detection limit of the HPLC-FLD method (0.01 µg L-1). One sample contained 0.57 µg L-1 saxitoxin, co-occurring with all four sxt genes studied. No correlation between PST and sxt gene occurrence or copy numbers was observed. A. gracile and C. raciborskii occurred in 92% and 50% of samples, respectively, containing PSTs, sxt genes or both. In conclusion, the results confirm that potential PST producers constitute an established subpopulation of cyanobacteria in Polish freshwater lakes. However, none of the sxt genes targeted in this study could serve as a reliable marker for active PST biosynthesis.

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“…Among these, saxitoxins and structurally similar compounds (gonyautoxins) bind to voltage gated sodium channels preventing the flow of sodium ions and action potentials [258][259][260]. Saxitoxin also modifies the voltage gating processes in K + channels and blocks L-type Ca 2+ channels [261,262]. Thus early symptoms of saxitoxin poisoning are tingling or burning of the lips, tongue and throat.…”

Section: Saxitoxinmentioning

confidence: 99%

Cyanobacterial Toxins of the Laurentian Great Lakes, their Toxicological Effects, and Numerical Limits in Drinking Water

Miller

Beversdorf

Weirich

et al. 2017

Preprint

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Cyanobacteria are ubiquitous phototrophic bacteria that inhabit diverse environments across the planet. They dominate many eutrophic lakes impacted by excess nitrogen (N) and phosphorus (P) forming dense accumulations of biomass known as cyanobacterial harmful algal blooms or cyanoHABs. Their dominance in eutrophic lakes is attributed to a variety of unique adaptations including N and P concentrating mechanisms, N fixation, colony formation that inhibits predation, vertical movement via gas vesicles, and the production of toxic or otherwise bioactive molecules. While some of these molecules have been explored for their medicinal benefits, others are potent toxins harmful to humans, animals, and other wildlife known as cyanotoxins. In humans these cyanotoxins affect various tissues, including the liver, central and peripheral nervous system, kidneys, and reproductive organs among others. They induce acute effects at low doses in the parts-per-billion range and some are tumor promoters linked to chronic diseases such as liver and colorectal cancer. The occurrence of cyanoHABs and cyanotoxins in lakes presents challenges for maintaining safe recreational aquatic environments and the production of potable drinking water. CyanoHABs are a growing problem in the North American (Laurentian) Great Lakes basin. This review summarizes information on the occurrence of cyanoHABs in the Great Lakes, toxicological effects of cyanotoxins, and appropriate numerical limits on cyanotoxins in finished drinking water.

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Saxitoxin Blocks L-TypeI_Ca

Cited by 124 publications

References 25 publications

Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria

Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria

First report of cyanobacterial paralytic shellfish toxin biosynthesis genes and paralytic shellfish toxin production in Polish freshwater lakes

Cyanobacterial Toxins of the Laurentian Great Lakes, their Toxicological Effects, and Numerical Limits in Drinking Water

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