Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish toxin. Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic shellfish poisoning (PSP). The term saxitoxin originates from the genus name of the butter clam (Saxidomus) from which it was first isolated. But the term saxitoxin can also refer to the entire suite of more than 50 structurally related neurotoxins (known collectively as "saxitoxins") produced by protists, algae and cyanobacteria which includes saxitoxin itself (STX), neosaxitoxin (NSTX), gonyautoxins (GTX) and decarbamoylsaxitoxin (dcSTX). Saxitoxin has a large environmental and economic impact, as its presence in bivalve shellfish such as mussels, clams, oysters and scallops frequently leads to bans on commercial and recreational shellfish harvesting in many temperate coastal waters around the world including the Northeastern and Western United States, Western Europe, East Asia, Australia, New Zealand, and South Africa. In the United States, paralytic shellfish poisoning has occurred in California, Oregon, Washington, Alaska, and New England.
Source in nature Saxitoxin is a neurotoxin naturally produced by certain species of marine dinoflagellates (Alexandrium sp., Gymnodinium sp., Pyrodinium sp.) and freshwater cyanobacteria (Dolichospermum cicinale sp., some Aphanizomenon spp., Cylindrospermopsis sp., Lyngbya sp., Planktothrix sp.) Saxitoxin accumulates in "planktivorous invertebrates, including mollusks (bivalves and gastropods), crustaceans, and echinoderms". Saxitoxin has also been found in at least twelve marine puffer fish species in Asia and one freshwater fish (tilapia) in Brazil. The ultimate source of STX is often still uncertain. The dinoflagellate Pyrodinium bahamense is the source of STX found in Florida. Recent research shows the detection of STX in the skin, muscle, viscera, and gonads of "Indian River Lagoon" southern puffer fish, with the highest concentration (22,104 μg STX eq/100 g tissue) measured in the ovaries. Even after a year of captivity, Landsberg et al. found the skin mucus remained highly toxic. The concentrations in puffer fish from the United States are similar to those found in the Philippines, Thailand, Japan, and South American countries. Puffer fish also accumulate a structurally distinct toxin, tetrodotoxin.
Structure and synthesis Saxitoxin dihydrochloride is an amorphous hygroscopic solid, but X-ray crystallography of crystalline derivatives enabled the structure of saxitoxin to be determined. Oxidation of saxitoxin generates a highly fluorescent purine derivative which has been utilized to detect its presence. Several total syntheses of saxitoxin have been accomplished.
Mechanism of action
Saxitoxin is a neurotoxin that acts as a selective, reversible, voltage-gated sodium channel blocker. One of the most potent known natural toxins, it acts on the voltage-gated sodium channels of neurons, preventing normal cellular function and leading to paralysis. The voltage-gated sodium channel is essential for normal neuronal functioning. It exists as integral membrane proteins interspersed along the axon of a neuron and possessing four domains that span the cell membrane. Opening of the voltage-gated sodium channel occurs when there is a change in voltage or some ligand binds in the right way. It is of foremost importance for these sodium channels to function properly, as they are essential for the propagation of an action potential. Without this ability, the nerve cell becomes unable to transmit signals and the region of the body that it innervates is cut off from the nervous system. This may lead to paralysis of the affected region, as in the case of saxitoxin. Saxitoxin binds reversibly to the sodium channel. It binds directly in the pore of the channel protein, occluding the opening, and preventing the flow of sodium ions through the membrane. This leads to the nervous shutdown described above.
Biosynthesis Although the biosynthesis of saxitoxin seems complex, organisms from two different kingdoms, indeed two different domains, species of marine dinoflagellates and freshwater cyanobacteria are capable of producing these toxins. While the prevailing theory of production in dinoflagellates was through symbiotic mutualism with cyanobacteria, evidence has emerged suggesting that dinoflagellates themselves also possess the genes required for saxitoxin synthesis. Saxitoxin biosynthesis is the first non-terpene alkaloid pathway described for bacteria, though the exact mechanism of saxitoxin biosynthesis is still essentially a theoretical model. The precise mechanism of how substrates bind to enzymes is still unknown, and genes involved in the biosynthesis of saxitoxin are either putative or have only recently been identified. Two biosyntheses have been proposed in the past. Earlier versions differ from a more recent proposal by Kellmann, et al. based on both biosynthetic considerations as well as genetic evidence not available at the time of the first proposal. The more recent model describes a STX gene cluster (Sxt) used to obtain a more favorable reaction. The most recent reaction sequence of Sxt in cyanobacteria is as follows. Refer to the diagram for a detailed biosynthesis and intermediate structures.
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