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Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish
toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...
(PST). Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic
algal bloom An algal bloom or algae bloom is a rapid increase or accumulation in the population of algae in freshwater or marine water systems. It is often recognized by the discoloration in the water from the algae's pigments. The term ''algae'' encompass ...
s, is responsible for the illness known as
paralytic shellfish poisoning Paralytic shellfish poisoning (PSP) is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks (such as mussels, clams, oysters and scallops). These shellfi ...
(PSP). The term saxitoxin originates from the genus name of the butter clam (''
Saxidomus ''Saxidomus'', common name the "Washington clams", is a genus of large edible saltwater clams, marine bivalve mollusks in the family Veneridae, the Venus clams. The species '' Saxidomus gigantea'' is known as the "butter clam". The term for sax ...
'') 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 Neosaxitoxin (NSTX) is included, as other saxitoxin-analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine al ...
(NSTX),
gonyautoxin Gonyautoxins (GTX) are a few similar toxic molecules that are naturally produced by algae. They are part of the group of saxitoxins, a large group of neurotoxins along with a molecule that is also referred to as saxitoxin (STX), neosaxitoxin (NSTX ...
s (GTX) and
decarbamoylsaxitoxin Decarbamoylsaxitoxin, abbreviated as dcSTX, is a neurotoxin which is naturally produced in dinoflagellate. DcSTX is one of the many analogues of saxitoxin (STX). Saxitoxin is a tricyclic alkaloid compound, which has multiple structural related n ...
(dcSTX). Saxitoxin has a large environmental and economic impact, as its presence in bivalve shellfish such as
mussels Mussel () is the common name used for members of several families of bivalve molluscs, from saltwater and freshwater habitats. These groups have in common a shell whose outline is elongated and asymmetrical compared with other edible clams, which ...
,
clams Clam is a common name for several kinds of bivalve molluscs. The word is often applied only to those that are edible and live as infauna, spending most of their lives halfway buried in the sand of the seafloor or riverbeds. Clams have two ...
, oysters and
scallops Scallop () is a common name that encompasses various species of Marine (ocean), marine bivalve mollusc, mollusks in the Taxonomy (biology), taxonomic Family (biology), family Pectinidae, the scallops. However, the common name "scallop" is also s ...
frequently leads to bans on commercial and recreational shellfish harvesting in many temperate coastal waters around the world including the Northeastern and
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,
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,
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, Australia,
New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island count ...
, and
South Africa South Africa, officially the Republic of South Africa (RSA), is the Southern Africa, southernmost country in Africa. It is bounded to the south by of coastline that stretch along the Atlantic Ocean, South Atlantic and Indian Oceans; to the ...
. In the United States, paralytic shellfish poisoning has occurred in
California California is a state in the Western United States, located along the Pacific Coast. With nearly 39.2million residents across a total area of approximately , it is the most populous U.S. state and the 3rd largest by area. It is also the m ...
,
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,
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,
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, and
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.


Source in nature

Saxitoxin is a neurotoxin naturally produced by certain species of marine
dinoflagellates The dinoflagellates (Greek δῖνος ''dinos'' "whirling" and Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered algae. Dinoflagellates a ...
( ''Alexandrium'' sp., ''
Gymnodinium ''Gymnodinium'' is a genus of dinoflagellates, a type of marine and freshwater plankton. It is one of the few naked dinoflagellates, or species lacking armor known as cellulosic plates. Since 2000, the species which had been considered to be par ...
'' sp., '' Pyrodinium'' sp.) and freshwater cyanobacteria ('' Dolichospermum cicinale'' sp., some '' Aphanizomenon'' spp., '' Cylindrospermopsis'' sp., ''
Lyngbya ''Lyngbya'' is a genus of cyanobacteria, unicellular autotrophs that form the basis of the oceanic food chain. As a result of recent genetic analyses, several new genera were erected from this genus: ''e.g.'', ''Moorea'', '' Limnoraphis'', '' O ...
'' sp., ''
Planktothrix ''Planktothrix'' is a diverse genus of filamentous cyanobacteria observed to amass in algal blooms in water ecosystems across the globe. Like all Oscillatoriales, ''Planktothrix'' species have no heterocysts and no akinetes. Planktothrix are ...
'' sp.) Saxitoxin accumulates in "planktivorous
invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordat ...
, including mollusks (bivalves and
gastropods The gastropods (), commonly known as snails and slugs, belong to a large taxonomic class of invertebrates within the phylum Mollusca called Gastropoda (). This class comprises snails and slugs from saltwater, from freshwater, and from land. The ...
),
crustaceans Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean gro ...
, and echinoderms". Saxitoxin has also been found in at least 12 marine
puffer fish Tetraodontidae is a family of primarily marine and estuarine fish of the order Tetraodontiformes. The family includes many familiar species variously called pufferfish, puffers, balloonfish, blowfish, blowies, bubblefish, globefish, swellfish ...
species in Asia and one freshwater fish
tilapia Tilapia ( ) is the common name for nearly a hundred species of cichlid fish from the coelotilapine, coptodonine, heterotilapine, oreochromine, pelmatolapiine, and tilapiine tribes (formerly all were "Tilapiini"), with the economically most ...
in
Brazil Brazil ( pt, Brasil; ), officially the Federative Republic of Brazil (Portuguese: ), is the largest country in both South America and Latin America. At and with over 217 million people, Brazil is the world's fifth-largest country by area ...
. However, the ultimate source of STX is often still uncertain. The dinoflagellate '' Pyrodinium bahamense'' is the source of STX found in
Florida Florida is a state located in the Southeastern region of the United States. Florida is bordered to the west by the Gulf of Mexico, to the northwest by Alabama, to the north by Georgia, to the east by the Bahamas and Atlantic Ocean, and to ...
. 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 The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
. 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 Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovere ...
.


Structure and synthesis

Saxitoxin di
hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative n ...
is an amorphous
hygroscopic Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substan ...
solid, but
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
of crystalline derivatives enabled the structure of saxitoxin to be determined.
Oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
of saxitoxin generates a highly
fluorescent Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, ...
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
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 Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels. Extracellular The following naturally-produced substances block sodium channels by binding to and occluding the extracellular pore opening ...
. 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 protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...
s interspersed along the
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
of a neuron and possessing four domains that span the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
. Opening of the voltage-gated sodium channel occurs when there is a change in
voltage Voltage, also known as electric pressure, electric tension, or (electric) potential difference, is the difference in electric potential between two points. In a static electric field, it corresponds to the work needed per unit of charge to ...
or some
ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
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 An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
. Without this ability, the nerve cell becomes unable to transmit signals and the region of the body that it enervates is cut off from the
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
. 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 Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
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
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s 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. # It begins with the loading of the
acyl carrier protein The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene ...
(ACP) with acetate from acetyl-CoA, yielding intermediate 1. # This is followed by SxtA-catalyzed methylation of acetyl-ACP, which is then converted to propionyl-ACP, yielding intermediate 2. # Later, another SxtA performs a
Claisen condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. It is named after Ra ...
reaction between propionyl-ACP and arginine producing intermediate 4 and intermediate 3. # SxtG transfers an amidino group from an arginine to the α-amino group of intermediate 4 producing intermediate 5. # Intermediate 5 then undergoes retroaldol-like condensation by SxtBC, producing intermediate 6. # SxtD adds a double bond between C-1 and C-5 of intermediate 6, which gives rise to the 1,2-H shift between C-5 and C-6 in intermediate 7. # SxtS performs an
epoxidation In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...
of the double bond yielding intermediate 8, and then an opening of the epoxide to an
aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
, forming intermediate 9. # SxtU reduces the terminal aldehyde group of the STX intermediate 9, thus forming intermediate 10. # SxtIJK catalyzes the transfer of a carbamoyl group to the free hydroxyl group on intermediate 10, forming intermediate 11. # SxtH and SxtT, in conjunction with SxtV and the SxtW gene cluster, perform a similar function which is the consecutive hydroxylation of C-12, thus producing saxitoxin and terminating the STX biosynthetic pathway.


Illness and poisoning


Toxicology

Saxitoxin is highly toxic to
guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus '' Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ...
s, fatal at only 5 μg/kg when injected intramuscularly. The lethal doses (
LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...
) for mice are very similar with varying administration routes: i.v. is 3.4 μg/kg, i.p. is 10 μg/kg and p.o. is 263 μg/kg. The oral LD50 for humans is 5.7 μg/kg, therefore approximately 0.57 mg of saxitoxin (1/8th of a medium-sized grain of sand) is lethal if ingested and the lethal dose by injection is about 1/10th of that (approximately 0.6 μg/kg). The human inhalation toxicity of aerosolized saxitoxin is estimated to be 5 mg·min/m3. Saxitoxin can enter the body via open wounds and a lethal dose of 50 μg/person by this route has been suggested.


Illness in humans

The human illness associated with ingestion of harmful levels of saxitoxin is known as
paralytic shellfish poisoning Paralytic shellfish poisoning (PSP) is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks (such as mussels, clams, oysters and scallops). These shellfi ...
, or PSP, and saxitoxin and its derivatives are often referred to as "PSP toxins". The medical and environmental importance of saxitoxin derives from the consumption of contaminated shellfish and certain finfish which can concentrate the toxin from dinoflagellates or cyanobacteria. The blocking of neuronal
sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chann ...
s which occurs in PSP produces a
flaccid paralysis Flaccid paralysis is a neurological condition characterized by weakness or paralysis and reduced muscle tone without other obvious cause (e.g., trauma). This abnormal condition may be caused by disease or by trauma affecting the nerves associ ...
that leaves its victim calm and conscious through the progression of symptoms. Death often occurs from
respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
. PSP toxins have been implicated in various marine animal mortalities involving trophic transfer of the toxin from its algal source up the food chain to higher
predator Predation is a biological interaction where one organism, the predator, kills and eats another organism, its prey. It is one of a family of common feeding behaviours that includes parasitism and micropredation (which usually do not kill th ...
s. Studies in animals have shown that the lethal effects of saxitoxin can be reversed with 4-aminopyridine, but there are no studies on human subjects. As with any paralytic agent, mouth-to-mouth resuscitation or artificial ventilation of any means will keep a poisoned victim alive until
antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...
is administered or the poison wears off.


Military interest

Saxitoxin, by virtue of its extremely low
LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...
, readily lends itself to weaponization. In the past, it was considered for military use by the United States and was developed as a
chemical weapon A chemical weapon (CW) is a specialized munition that uses chemicals formulated to inflict death or harm on humans. According to the Organisation for the Prohibition of Chemical Weapons (OPCW), this can be any chemical compound intended as a ...
by the
US military The United States Armed Forces are the Military, military forces of the United States. The armed forces consists of six Military branch, service branches: the United States Army, Army, United States Marine Corps, Marine Corps, United States N ...
. It is known that saxitoxin was developed for both overt military use as well as for covert purposes by the CIA. Among weapons stockpiles were M1 munitions that contained either saxitoxin or botulinum toxin or a mixture of both. On the other hand, the CIA is known to have issued a small dose of saxitoxin to U-2 spy plane pilot
Francis Gary Powers Francis Gary Powers (August 17, 1929 – August 1, 1977) was an American pilot whose Central Intelligence Agency (CIA) Lockheed U-2 spy plane was shot down while flying a reconnaissance mission in Soviet Union airspace, causing the 1960 U-2 in ...
in the form of a small injection hidden within a silver dollar, for use in the event of his capture and detainment. After the 1969 ban on
biological warfare Biological warfare, also known as germ warfare, is the use of biological toxins or infectious agents such as bacteria, viruses, insects, and fungi with the intent to kill, harm or incapacitate humans, animals or plants as an act of war. ...
by President
Nixon Richard Milhous Nixon (January 9, 1913April 22, 1994) was the 37th president of the United States, serving from 1969 to 1974. A member of the Republican Party, he previously served as a representative and senator from California and was ...
, the US stockpiles of saxitoxin were destroyed, and development of saxitoxin as a military weapon ceased. However, in 1975 the CIA reported to Congress that it had kept a small amount of saxitoxin and cobra venom against Nixon's orders which was then destroyed or distributed to researchers. It is listed in
schedule 1 Schedule 1 may refer to: * Schedule I Controlled Substances within the US Controlled Substances Act * Schedule I Controlled Drugs and Substances within the Canadian Controlled Drugs and Substances Act * Schedule I Psychotropic Substances within t ...
of the Chemical Weapons Convention. The United States military isolated saxitoxin and assigned it the chemical weapon designation ''TZ''.


See also

* * * * * * * * * * *


References


External links



Paralytic Shellfish Poisoning

Neil Edwards. The Chemical Laboratories. School of Chemistry, Physics & Environmental Science. University of Sussex at Brighton. Saxitoxin - from food poisoning to chemical warfare
Toxic cyanobacteria in water: A guide to their public health consequences, monitoring and management.
Edited by Ingrid Chorus and Jamie Bartram, 1999. Published by World Health Organization. {{Authority control Alkaloids Biological toxin weapons Marine neurotoxins Carbamates Guanidine alkaloids Phycotoxins Cyanotoxins Sodium channel blockers Bacterial alkaloids Voltage-gated sodium channel blockers Non-protein ion channel toxins Geminal diols Heterocyclic compounds with 3 rings Nitrogen heterocycles