Domoic acid

Last updated
Domoic acid
Domoic acid.svg
Names
Preferred IUPAC name
(2S,3S,4S)-4-[(2Z,4E,6R)-6-Carboxyhepta-2,4-dien-2-yl]-3-(carboxymethyl)pyrrolidine-2-carboxylic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.159.099 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 630-802-1
PubChem CID
UNII
  • InChI=1S/C15H21NO6/c1-8(4-3-5-9(2)14(19)20)11-7-16-13(15(21)22)10(11)6-12(17)18/h3-5,9-11,13,16H,6-7H2,1-2H3,(H,17,18)(H,19,20)(H,21,22)/b5-3+,8-4-/t9-,10+,11-,13+/m1/s1 Yes check.svgY
    Key: VZFRNCSOCOPNDB-AOKDLOFSSA-N Yes check.svgY
  • InChI=1/C15H21NO6/c1-8(4-3-5-9(2)14(19)20)11-7-16-13(15(21)22)10(11)6-12(17)18/h3-5,9-11,13,16H,6-7H2,1-2H3,(H,17,18)(H,19,20)(H,21,22)/b5-3+,8-4-/t9-,10+,11-,13+/m1/s1
    Key: VZFRNCSOCOPNDB-AOKDLOFSBM
  • O=C(O)[C@H]1NC[C@H](/C(=C\C=C\[C@H](C(=O)O)C)C)[C@@H]1CC(=O)O
Properties
C15H21NO6
Molar mass 311.334 g·mol−1
Density 1.273 g/cm3
Vapor pressure 2.62×10−16 mmHg (34.9 fPa)
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H302, H312, H332
P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Domoic acid (DA) is a kainic acid-type neurotoxin that causes amnesic shellfish poisoning (ASP). [1] It is produced by algae and accumulates in shellfish, sardines, and anchovies. When sea lions, otters, cetaceans, humans, and other predators eat contaminated animals, poisoning may result. Exposure to this compound affects the brain, causing seizures, and possibly death. [2]

Contents

History

There has been little use of domoic acid throughout history except for in Japan, where it has been used as an anthelmintic for centuries. [3] Domoic acid was first isolated in 1959 from a species of red algae, Chondria armata , in Japan, which is commonly referred to as dōmoi (ドウモイ) in the Tokunoshima dialect, or hanayanagi. Poisonings in history have been rare, or undocumented; however, it is thought that the increase in human activities is resulting in an increasing frequency of harmful algal blooms along coastlines in recent years. In 2015, the North American Pacific coast was heavily impacted by an algal bloom, consisting predominantly of the domoic acid-producing pennate diatom, Pseudo-nitzschia. Consequently, elevated levels of domoic acid were measured in stranded marine mammals, prompting the closure of beaches and damaging razor clam, rock crab and Dungeness crab fisheries. [4]

In 1961, seabirds attacked the Capitola area in California, and though it was never confirmed, it was later hypothesized that they were under the influence of domoic acid. [5]

In 1987, in Prince Edward Island, Canada, there was a shellfish poisoning resulting in 3 deaths. Blue mussels (Mytulis edulis) contaminated with domoic acid were blamed. [6]

Domoic acid has been suggested to have been involved in an incident which took place on June 22, 2006, when a California brown pelican flew through the windshield of a car on the Pacific Coast Highway. [7]

On Friday, June 14, 2019, a teenager was attacked and injured by a sea lion that was alleged to be under the influence of domoic acid in Pismo Beach on the Central California coast. [8]

Chemistry

General

Domoic acid is a structural analog of kainic acid, proline, and endogenous excitatory neurotransmitter glutamate. [9] Ohfune and Tomita, who wanted to investigate its absolute stereochemistry, were the first and only to synthesize domoic acid in 1982. [1]

Biosynthesis

In 1999, using 13C- and 14C-labelled precursors, the biosynthesis of domoic acid in the diatom genus Pseudo-nitzschia was examined. After addition of [1,2-13C2]-acetate, NMR spectroscopy showed enrichment of every carbon in domoic acid, indicating incorporation of the carbon isotopes. This enrichment was consistent with two biosynthetic pathways. The labeling pattern determined that domoic acid can be biosynthesized by an isoprenoid intermediate in combination with a tricarboxylic acid (TCA) cycle intermediate. [10]

In 2018, using growth conditions known to induce domoic acid production in Pseudo-nitzschia multiseries, transcriptome sequencing successfully identified candidate domoic acid biosynthesis genes responsible for the pyrrolidine core. [11] These domoic acid biosynthesis genes, or ‘Dab’ enzymes were heterologously expressed, characterized, and annotated as dabA (terpene cyclase), dabB (hypothetical protein), dabC (α-ketoglutarate–dependent dioxygenase), and dabD (CYP450).

Simplified domoic acid biosynthetic pathway, with all pertinent structures, enzymes, and cofactors listed as described by Brunson et al., in their article "Biosynthesis of the neurotoxin domoic acid in a bloom-forming diatom". Domoic Acid Biosynthesis.png
Simplified domoic acid biosynthetic pathway, with all pertinent structures, enzymes, and cofactors listed as described by Brunson et al., in their article "Biosynthesis of the neurotoxin domoic acid in a bloom-forming diatom".

Domoic acid biosynthesis begins with the DabA-catalyzed geranylation of L-glutamic acid (L-Glu) with geranyl pyrophosphate (GPP) to form N-geranyl-L-glutamic acid (L-NGG). DabD then performs three successive oxidation reactions at the 7′-methyl of L-NGG to produce 7′-carboxy-L-NGG, which is then cyclized by DabC to generate the naturally occurring isodomoic acid A. Finally, an uncharacterized isomerase could convert isodomoic acid A to domoic acid. Further investigation is needed to resolve the final isomerization reaction to complete the pathway to Domoic acid.

Synthesis

Synthesis of Domoic Acid as described by Jonathan Clayden, Benjamin Read and Katherine R. Hebditch, in their article Chemistry of domoic acid, isodomoic acids, and their analogues. Domoic Acid Synthesis.pdf
Synthesis of Domoic Acid as described by Jonathan Clayden, Benjamin Read and Katherine R. Hebditch, in their article Chemistry of domoic acid, isodomoic acids, and their analogues.

Using intermediates 5 and 6, a Diels-Alder reaction produced a bicyclic compound (7). 7 then underwent ozonolysis to open the six-membered ring leading to selenide (8). 8 was then deselenated to form 9 (E-9 and Z-9), lastly leading to the formation of (-) domoic acid. [1]

Mechanism of action

The effects of domoic acid have been attributed to several mechanisms, but the one of concern is through glutamate receptors. Domoic acid is an excitatory amino acid analogue of glutamate; a neurotransmitter in the brain that activates glutamate receptors. Domoic acid has a very strong affinity for these receptors, which results in excitotoxicity initiated by an integrative action on ionotropic glutamate receptors at both sides of the synapse, coupled with the effect of blocking the channel from rapid desensitization. In addition there is a synergistic effect with endogenous glutamate and N-Methyl-D-aspartate receptor agonists that contribute to the excitotoxicity.

In the brain, domoic acid especially damages the hippocampus and amygdaloid nucleus. It damages the neurons by activating AMPA and kainate receptors, causing an influx of calcium. Although calcium flowing into cells is normal, the uncontrolled increase of calcium causes the cells to degenerate. Because the hippocampus may be severely damaged, short-term memory loss occurs. It may also cause kidney damage – even at levels considered safe for human consumption, a new study in mice has revealed. The kidney is affected at a hundred times lower than the concentration allowed under FDA regulations. [12] [13]

Symptoms of domoic acid
HumansAnimals
vomitinghead weaving
nauseaseizures
diarrhea and abdominal cramps
within 24 hours of ingestion
bulging eyes
headachemucus from the mouth
dizzinessdisorientation and aggressiveness
confusion, disorientationdeath
loss of short-term memory
motor weakness
seizures
profuse respiratory secretions
cardiac arrhythmias
coma and possible death
References for all, unless otherwise noted: [6]

Toxicology

Domoic acid producing algal blooms are associated with the phenomenon of amnesic shellfish poisoning (ASP). Domoic acid can bioaccumulate in marine organisms such as shellfish, anchovies, and sardines that feed on the phytoplankton known to produce this toxin. It can accumulate in high concentrations in the tissues of these plankton feeders when the toxic phytoplankton are high in concentration in the surrounding waters. Domoic acid is a neurotoxin that inhibits neurochemical processes, causing short-term memory loss, brain damage, and, in severe cases, death in humans. In marine mammals, domoic acid typically causes seizures and tremors.

Studies have shown that there are no symptomatic effects in humans at levels of 0.5 mg/kg of body weight. In the 1987 domoic acid poisoning on Prince Edward Island concentrations ranging from 0.31 to 1.28 mg/kg of muscle tissue were noted in people that became ill (three of whom died). Dangerous levels of domoic acid have been calculated based on cases such as the one on Prince Edward island. The exact LD50 for humans is unknown; for mice the LD50 is 3.6 mg/kg. [6]

New research has found that domoic acid is a heat-resistant and very stable toxin, which can damage kidneys at concentrations that are 100 times lower than what causes neurological effects. [13]

Diagnosis and prevention

In order to be diagnosed and treated if poisoned, domoic acid must first be detected. Methods such as ELISA or probe development with polymerase chain reaction (PCR) may be used to detect the toxin or the organism producing this toxin. [14]

There is no known antidote available for domoic acid. Therefore, if poisoning occurs, it is advised to go quickly to a hospital. Cooking or freezing affected fish or shellfish tissue that are contaminated with domoic acid does not lessen the toxicity. [15]

As a public health concern, the concentration of domoic acid in shellfish and shellfish parts at point of sale should not exceed the current permissible limit of 20 mg/kg tissue. In addition, during processing shellfish, it is important to pay attention to environmental condition factors. [16]

On August 18, 1961, in Capitola and Santa Cruz, California there was an invasion of what people described as chaotic seabirds. These birds were believed to be under the influence of domoic acid, and it inspired a scene in Alfred Hitchcock's feature film The Birds . [17]

In the Elementary Season 1 Episode 13 "The Red Team", domoic acid was used as a poison to mimic Alzheimer's. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Toxin</span> Naturally occurring organic poison

A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919) and is derived from the word "toxic".

<span class="mw-page-title-main">Algal bloom</span> Spread of planktonic algae in water

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 encompasses many types of aquatic photosynthetic organisms, both macroscopic multicellular organisms like seaweed and microscopic unicellular organisms like cyanobacteria. Algal bloom commonly refers to the rapid growth of microscopic unicellular algae, not macroscopic algae. An example of a macroscopic algal bloom is a kelp forest.

<span class="mw-page-title-main">Neurotoxin</span> Toxin harmful to nervous tissue

Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.

<span class="mw-page-title-main">Excitotoxicity</span> Process that kills nerve cells

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.

<span class="mw-page-title-main">Cyanotoxin</span> Toxin produced by cyanobacteria

Cyanotoxins are toxins produced by cyanobacteria. Cyanobacteria are found almost everywhere, but particularly in lakes and in the ocean where, under high concentration of phosphorus conditions, they reproduce exponentially to form blooms. Blooming cyanobacteria can produce cyanotoxins in such concentrations that they can poison and even kill animals and humans. Cyanotoxins can also accumulate in other animals such as fish and shellfish, and cause poisonings such as shellfish poisoning.

<span class="mw-page-title-main">Saxitoxin</span> Paralytic shellfish toxin

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).

<span class="mw-page-title-main">Kainic acid</span> Chemical compound

Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervous system. Glutamate is produced by the cell's metabolic processes and there are four major classifications of glutamate receptors: NMDA receptors, AMPA receptors, kainate receptors, and the metabotropic glutamate receptors. Kainic acid is an agonist for kainate receptors, a type of ionotropic glutamate receptor. Kainate receptors likely control a sodium channel that produces excitatory postsynaptic potentials (EPSPs) when glutamate binds.

<span class="mw-page-title-main">Paralytic shellfish poisoning</span> Syndrome of 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. These shellfish are filter feeders and accumulate neurotoxins, chiefly saxitoxin, produced by microscopic algae, such as dinoflagellates, diatoms, and cyanobacteria. Dinoflagellates of the genus Alexandrium are the most numerous and widespread saxitoxin producers and are responsible for PSP blooms in subarctic, temperate, and tropical locations. The majority of toxic blooms have been caused by the morphospecies Alexandrium catenella, Alexandrium tamarense, Gonyaulax catenella and Alexandrium fundyense, which together comprise the A. tamarense species complex. In Asia, PSP is mostly associated with the occurrence of the species Pyrodinium bahamense.

Amnesic shellfish poisoning (ASP) is an illness caused by consumption of shellfish that contain the marine biotoxin called domoic acid. In mammals, including humans, domoic acid acts as a neurotoxin, causing permanent short-term memory loss, brain damage, and death in severe cases.

<span class="mw-page-title-main">Brevetoxin</span> Class of chemical compounds produced naturally

Brevetoxin (PbTx), or brevetoxins, are a suite of cyclic polyether compounds produced naturally by a species of dinoflagellate known as Karenia brevis. Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nerve cells, leading to disruption of normal neurological processes and causing the illness clinically described as neurotoxic shellfish poisoning (NSP).

<span class="mw-page-title-main">Oxalyldiaminopropionic acid</span> Chemical compound

Oxalyldiaminopropionic acid (ODAP) is a structural analogue of the neurotransmitter glutamate found in the grass pea Lathyrus sativus. It is the neurotoxin responsible for the motor neuron degeneration syndrome lathyrism.

<span class="mw-page-title-main">Neurotoxic shellfish poisoning</span> Syndrome of shellfish poisoning

Neurotoxic shellfish poisoning (NSP) is caused by the consumption of brevetoxins, which are marine toxins produced by the dinoflagellate Karenia brevis. These toxins can produce a series of gastrointestinal and neurological effects. Outbreaks of NSP commonly take place following harmful algal bloom (HAB) events, commonly referred to as "Florida red tide". Algal blooms are a naturally-occurring phenomenon, however their frequency has been increasing in recent decades at least in-part due to human activities, climate changes, and the eutrophication of marine waters. HABs have been occurring for all of documented history, evidenced by the Native Americans' understanding of the dangers of shellfish consumption during periods of marine bioluminescence. Blooms have been noted to occur as far north as North Carolina and are commonly seen alongside the widespread death of fish and sea birds. In addition to the effects on human health, the economic impact of HAB-associated shellfish toxin outbreaks can have significant economic implications as well due to not only the associated healthcare costs, but the adverse impact on the commercial shellfish industry.

<span class="mw-page-title-main">Harmful algal bloom</span> Population explosion of organisms that can kill marine life

A harmful algal bloom (HAB), or excessive algae growth, is an algal bloom that causes negative impacts to other organisms by production of natural algae-produced toxins, mechanical damage to other organisms, or by other means. HABs are sometimes defined as only those algal blooms that produce toxins, and sometimes as any algal bloom that can result in severely lower oxygen levels in natural waters, killing organisms in marine or fresh waters. Blooms can last from a few days to many months. After the bloom dies, the microbes that decompose the dead algae use up more of the oxygen, generating a "dead zone" which can cause fish die-offs. When these zones cover a large area for an extended period of time, neither fish nor plants are able to survive. Harmful algal blooms in marine environments are often called "red tides".

The Shellfish Association of Great Britain (SAGB) is a historic association that was founded as the Oyster Merchants' and Planters' Association in 1903, it was renamed the SAGB in 1969. They cover a wide range of topics within the shellfish industry, from trading to advice on nutritional standards and also the sustainability of the industry.

<i>Nitzschia</i> Genus of single-celled organisms

Nitzschia is a common pennate marine diatom. In the scientific literature, this genus, named after Christian Ludwig Nitzsch, is sometimes referred to incorrectly as Nitzchia, and it has many species described, which all have a similar morphology. In its current circumscription, Nitzschia is paraphyletic.

<i>Pseudo-nitzschia</i> Genus of marine planktonic diatoms

Pseudo-nitzschia is a marine planktonic diatom genus that accounts for 4.4% of pennate diatoms found worldwide. Some species are capable of producing the neurotoxin domoic acid (DA), which is responsible for the neurological disorder in humans known as amnesic shellfish poisoning (ASP). Currently, 58 species are known, 28 of which have been shown to produce DA. It was originally hypothesized that only dinoflagellates could produce harmful algal toxins, but a deadly bloom of Pseudo-nitzschia occurred in 1987 in the bays of Prince Edward Island, Canada, and led to an outbreak of ASP. Over 100 people were affected by this outbreak after consuming contaminated mussels; three people died. Since this event, no additional deaths have been attributed to ASP, though the prevalence of toxic diatoms and DA has increased worldwide. This anomaly is likely due to increased awareness of harmful algal blooms (HABs) and their implications for human and ecosystem health.

Phycotoxins are complex allelopathic chemicals produced by eukaryotic and prokaryotic algal secondary metabolic pathways. More simply, these are toxic chemicals synthesized by photosynthetic organisms. These metabolites are not harmful to the producer but may be toxic to either one or many members of the marine food web. This page focuses on phycotoxins produced by marine microalgae; however, freshwater algae and macroalgae are known phycotoxin producers and may exhibit analogous ecological dynamics. In the pelagic marine food web, phytoplankton are subjected to grazing by macro- and micro-zooplankton as well as competition for nutrients with other phytoplankton species. Marine bacteria try to obtain a share of organic carbon by maintaining symbiotic, parasitic, commensal, or predatory interactions with phytoplankton. Other bacteria will degrade dead phytoplankton or consume organic carbon released by viral lysis. The production of toxins is one strategy that phytoplankton use to deal with this broad range of predators, competitors, and parasites. Smetacek suggested that "planktonic evolution is ruled by protection and not competition. The many shapes of plankton reflect defense responses to specific attack systems". Indeed, phytoplankton retain an abundance of mechanical and chemical defense mechanisms including cell walls, spines, chain/colony formation, and toxic chemical production. These morphological and physiological features have been cited as evidence for strong predatory pressure in the marine environment. However, the importance of competition is also demonstrated by the production of phycotoxins that negatively impact other phytoplankton species. Flagellates are the principle producers of phycotoxins; however, there are known toxigenic diatoms, cyanobacteria, prymnesiophytes, and raphidophytes. Because many of these allelochemicals are large and energetically expensive to produce, they are synthesized in small quantities. However, phycotoxins are known to accumulate in other organisms and can reach high concentrations during algal blooms. Additionally, as biologically active metabolites, phycotoxins may produce ecological effects at low concentrations. These effects may be subtle, but have the potential to impact the biogeographic distributions of phytoplankton and bloom dynamics.

Dinotoxins are a group of toxins which are produced by flagellate, aquatic, unicellular protists called dinoflagellates. Dinotoxin was coined by Hardy and Wallace in 2012 as a general term for the variety of toxins produced by dinoflagellates. Dinoflagellates are an enormous group of marine life, with much diversity. With great diversity comes many different toxins, however, there are a few toxins that multiple species have in common.

Pseudo-nitzschia australis is a pennate diatom found in temperate and sub-tropic marine waters, such as off the coast of California and Argentina. This diatom is a Harmful Micro Algae that produces toxic effects on a variety of organisms through its production of domoic acid, a neurotoxin. Toxic effects have been observed in a variety of predatory organisms such as pelicans, sea lions, and humans. If exposed to a high enough dose, these predators will die as a result, and there is no known antidote. The potential indirect mortality associated with P. australis is of great concern to humans as toxic algae blooms, including blooms of P. australis, continue to increase in frequency and severity over recent years. Blooms of P. australis are believed to result from high concentrations of nitrates and phosphates in stream and river runoff, as well as coastal upwelling, which are also sources of other harmful algae blooms.

Mary Wilcox Silver is Professor Emerita at the University of California Santa Cruz. Silver is known for research on marine snow and harmful algal blooms, setting the stage for woman conducting research in the field, and for mentoring and teaching of graduate and undergraduate students.

References

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  18. "Elementary s01e13 Episode Script | SS". Springfield! Springfield!.