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 Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature nerv ...

along with a molecule that is also referred to as

saxitoxin Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish toxin (PST). Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic ...

(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) 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). Currently eight molecules are assigned to the group of gonyautoxins, known as gonyautoxin 1 (GTX-1) to gonyautoxin 8 (GTX-8). Ingestion of gonyautoxins through consumption of

mollusks Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant species of molluscs are recognized. The number of fossil species is esti ...

contaminated by toxic

algae Algae (; singular alga ) is an informal term for a large and diverse group of photosynthetic eukaryotic organisms. It is a polyphyletic grouping that includes species from multiple distinct clades. Included organisms range from unicellular mic ...

can cause a human illness called

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 shellfis ...

(PSP).

Natural sources

Gonyautoxins are naturally produced by several 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 are ...

species (''

Alexandrium Alexandreion (Greek), or Alexandrium (Latin), called Sartaba in the Mishna and Talmud and Qarn Sartaba in Arabic, was an ancient hilltop fortress constructed by the Hasmoneans between Scythopolis and Jerusalem on a pointy barren hill towering ...

'' sp., ''

Gonyaulax ''Gonyaulax'' is a genus of dinoflagellates with the type species ''Gonyaulax spinifera'' (Claparède et Lachmann) Diesing. ''Gonyaulax'' belongs to red dinoflagellates and commonly causes red tides. It secretes a poisonous toxin known as "saxit ...

'' sp., '' Protogonyaulax'' sp.).The Human Metabolome Database
/ref> The paralytic shellfish poisoning caused by these toxins is connected with dinoflagellate blooms known as “red tides”, even though the coloration of the water isn’t a necessity. The threshold concentration of the organisms that are capable to produce the toxins is lower than the lowest visually detectable concentration. Subsequently the toxins are taken up by shellfish and undergo

bioaccumulation Bioaccumulation is the gradual accumulation of substances, such as pesticides or other chemicals, in an organism. Bioaccumulation occurs when an organism absorbs a substance at a rate faster than that at which the substance is lost or eliminated ...

Structure

As part of the group of saxitoxins, the gonyautoxins have their structure based on the 2,6-diamino-4-methyl-pyrollo ,2-cpurin-10-ol skeleton (also known as the Saxitoxin-gonyautoxin skeleton). The different molecules only differ from each other by their substituents, some of them only by a mere

stereoisomerism In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

such as GTX-2 and GTX-3.Toronto Research Chemicals website
/ref> Gonyautoxins are detectable by means of

High Performance Liquid Chromatography High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...

(HPLC), which has been tested on mice., In 2009 a monoclonal antibody is developed to detect gonyautoxin 2 or 3 in aquatic products. The detection limit is measured to be lower than 0.74 micrograms per milliliter.

Synthesis

While the gonyautoxins are naturally available, a synthesis procedure of some of them is known as well. Gonyautoxin 2 can for example be synthesized from L-serine methyl ester, via gonyautoxin 3. In this process firstly the L-serine methyl ester is treated with

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 ...

, so that it can react to close the ring structure. The formed allyl is deprotected by the addition of SO₃CH₂CCl₃. Subsequently a RH-catalyzed amination reaction with guanidine is followed, forming the tricyclic frame of GTX-3. The relatively unstable intermediates of several reactions in this process are modified by using three protecting groups. Removing these groups gives 11β-hydrosaxitoxin as a product, which will then be sulfated on the C 11-alcohol. GTX-2 is formed by incubating the product in an aqueous solution at pH 8, in order to make the

epimerization In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is ...

at C11 still occur.

Poisoning and illness

Toxicology

Like every saxitoxin, the gonyautoxins are

and cause a disease known as

(PSP). For humans a dose of 1–4 mg of these toxins is already lethal.

Shellfish Shellfish is a colloquial and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater envir ...

can contain more than 10 micrograms of gonyautoxin per 100 gram weight, inducing that the consumption of a few

mussels Mussel () is the common name used for members of several families of bivalve mollusc Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,0 ...

can already be fatal for human. Each year approximately 2000 cases of PSP are reported, of which about 15% end deadly.

Mechanism of action

As neurotoxins, the gonyautoxins influence 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 th ...

. They can bind with high affinity at the site 1 of the α-subunit of the voltage dependent

sodium channels 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 ...

in the

postsynaptic membrane Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

. These channels are responsible for initiating the action potentials, after the

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

. The binding of PSP toxins prevents the generation and propagation of these potentials and hence blocks the synaptic function.

Symptoms

The symptoms are the typical symptoms of a shellfish toxication. It starts with prickling in the face, which will later spread out over the body. This will be followed by numbness and headaches. In extreme cases, the possibility of vertigos exists as well. Over time the pulse increases and muscle pain occurs. Furthermore, blindness and vision disorders are also possible symptoms. Death is most likely to occur within the first twelve hours, caused by paralysis of the respiratory tract. Most patients who manage to keep up for this time, will survive the poisoning.

Detoxification

Biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected w ...

in the human body occurs as a first phase detoxification by

oxidizing 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 d ...

the gonyautoxin molecule. The formed products are other oxidized forms of gonyautoxins. In the second phase detoxification step a

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...

takes place which produces glucuronic-GTX, which has an increased

hydrophilicity A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...

in comparison to the GTX and can hence be excreted more easily.

Treatment

Since no

antitoxin An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacterium, bacteria in response to toxin exposure. Although they are most effective in neutralizing toxins, the ...

has been found yet, the treatment is in first line

symptomatic Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

for a paralytic shellfish poisoning. Aside a possible artificial respiration, the treatment with

charcoal Charcoal is a lightweight black carbon residue produced by strongly heating wood (or other animal and plant materials) in minimal oxygen to remove all water and volatile constituents. In the traditional version of this pyrolysis process, cal ...

is an option as well because shellfish toxins are likely to be absorbed by this substance. Potentially the strongly discussed treatment with

neostigmine Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...

ephedrine Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...

, or DL-amphetamine can be helpful as well.

Other uses

Gonyautoxins can be used as treatment against acute or chronic anal fissures. The toxins help the muscle to relax and hence kill the pain. In a study, the bleedings of the poisoned patients stopped within 48 hours. This is thanks to a temporary paralysis at the injection-area, which appears to last for over one week.

References

{{Reflist Marine neurotoxins Guanidine alkaloids Carbamates Geminal diols Sulfate esters