 | |
| 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 |
| EC Number |
|
| UNII | |
| |
| |
| 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: | |
 | |
| 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 theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Domoic acid (DA) is akainic acid–typeneurotoxin that causesamnesic shellfish poisoning (ASP).[1] It is produced byalgae and accumulates inshellfish,sardines, andanchovies. When sea lions, otters, cetaceans, humans, and other predators eat contaminated animals, poisoning may result. Exposure to this compound affects the brain, causing seizures, delirium and possibly death.[2]
There has been little use of domoic acid throughout history except for inJapan, where it has been used as ananthelmintic 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 asdōmoi (ドウモイ) in theTokunoshima dialect, orhanayanagi. 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 harmfulalgal 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 theCapitola area inCalifornia, and though it was never confirmed, it was later hypothesized that they were under the influence of domoic acid.[5]
In 1987, inPrince Edward Island, Canada, there was a shellfish poisoning resulting in 3 deaths.Blue mussels (Mytilus 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 aCalifornia brown pelican flew through the windshield of a car on thePacific Coast Highway.[7]
On Friday, June 14, 2019, a teenager was attacked and injured by asea lion that was alleged to be under the influence of domoic acid inPismo Beach on the CentralCalifornia coast.[8]
Domoic acid is a structural analog ofkainic acid,proline, and endogenous excitatory neurotransmitterglutamate.[9] Ohfune and Tomita, who wanted to investigate its absolute stereochemistry, were the first and only to synthesize domoic acid in 1982.[1]
In 1999, using13C- and14C-labelled precursors, the biosynthesis of domoic acid in the diatom genusPseudo-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 anisoprenoid intermediate in combination with atricarboxylic acid (TCA) cycle intermediate.[10]
In 2018, using growth conditions known to induce domoic acid production inPseudo-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 asdabA (terpene cyclase),dabB (hypothetical protein),dabC (α-ketoglutarate–dependent dioxygenase), anddabD (CYP450).
Domoic acid biosynthesis begins with the DabA-catalyzed geranylation of L-glutamic acid (L-Glu) with geranyl pyrophosphate (GPP) to formN-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.
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]
The effects of domoic acid have been attributed to several mechanisms, but the one of concern is throughglutamate 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 inexcitotoxicity initiated by an integrative action onionotropic 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 thehippocampus andamygdaloid nucleus. It damages the neurons by activatingAMPA andkainate 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 underFDA regulations.[12][13]
| Humans | Animals |
|---|---|
| vomiting | head weaving |
| nausea | seizures |
| diarrhea and abdominal cramps within 24 hours of ingestion | bulging eyes |
| headache | mucus from the mouth |
| dizziness | disorientation and aggressiveness |
| confusion, disorientation | death |
| loss of short-term memory | |
| motor weakness | |
| seizures | |
| profuse respiratory secretions | |
| cardiac arrhythmias | |
| coma and possible death | |
| References for all, unless otherwise noted:[6] | |
Domoic acid producing algal blooms are associated with the phenomenon ofamnesic shellfish poisoning (ASP). Domoic acid canbioaccumulate in marine organisms such as shellfish, anchovies, and sardines that feed on thephytoplankton 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 aneurotoxin 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 exactLD50 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]
In order to be diagnosed and treated if poisoned, domoic acid must first be detected. Methods such asELISA or probe development withpolymerase 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, inCapitola andSanta 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 inAlfred Hitchcock's feature filmThe Birds.[17]
In theElementary Season 1 Episode 13 "The Red Team", domoic acid was used as a poison to mimicAlzheimer's.[18]
In the TV showBunk'd, domoic acid somehow combines with fog to create a chemical that causes people to lose memory or gain alter-egos when inhaled.
