Gonyautoxin
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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 n ...
along with a molecule that is also referred to as
saxitoxin 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 she ...
(STX), neosaxitoxin (NSTX) and decarbamoylsaxitoxin (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 a phylum of protostomic invertebrate animals, whose members are known as molluscs or mollusks (). Around 76,000 extant species of molluscs are recognized, making it the second-largest animal phylum after Arthropoda. The num ...
contaminated by toxic
algae Algae ( , ; : alga ) is an informal term for any organisms of a large and diverse group of photosynthesis, photosynthetic organisms that are not plants, and includes species from multiple distinct clades. Such organisms range from unicellular ...
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 shellfi ...
(PSP).


Natural sources

Gonyautoxins are naturally produced by several marine
dinoflagellates The Dinoflagellates (), also called Dinophytes, are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered protists. Dinoflagellates are mostly marine plankton, but they are also commo ...
species ('' Alexandrium'' 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 can produce yesotoxins: for example, strai ...
'' 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 faster than it can be lost or eliminated by catabolism and excretion. T ...
.


Structure

As part of the group of saxitoxins, the gonyautoxins have their structure based on the 2,6-diamino-4-methyl-pyrollo
,2-c The comma is a punctuation mark that appears in several variants in different languages. Some typefaces render it as a small line, slightly curved or straight, but inclined from the vertical; others give it the appearance of a miniature fille ...
purin-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 specific components in mixtures. The mixtures can origina ...
(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 () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
, 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 at C11 still occur.


Poisoning and illness


Toxicology

Like every saxitoxin, the gonyautoxins are
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 n ...
and cause a disease 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). For humans a dose of 1–4 mg of these toxins is already lethal.
Shellfish Shellfish, in colloquial and fisheries usage, are exoskeleton-bearing Aquatic animal, aquatic invertebrates used as Human food, food, including various species of Mollusca, molluscs, crustaceans, and echinoderms. Although most kinds of shellfish ...
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 molluscs, from saltwater and freshwater habitats. These groups have in common a shell whose outline is elongated and asymmetrical compared with other edible clams, whic ...
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 complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. 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. Classification They are classified into 2 types: Function In e ...
in the postsynaptic membrane. These channels are responsible for initiating the action potentials, after the
synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
. 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 ...
in the human body occurs as a first phase detoxification by
oxidizing Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
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 gly ...
takes place which produces glucuronic-GTX, which has an increased hydrophilicity 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 diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...
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, ca ...
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 and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...
, 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.


See also

*
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 ...
*
Action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
*
Harmful algal bloom A harmful algal bloom (HAB), or excessive algae growth, sometimes called a red tide in marine environments, is an algal bloom that causes negative impacts to other organisms by production of natural algae-produced toxins, water deoxygenation, ...
*
Saxitoxin 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 she ...


References

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