Editing Domoic acid

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|Section2={{Chembox Properties
| C = 15 | H = 21 | N = 1 | O = 6
| Appearance =
| Density = 1.273 g/cm<sup>3</sup>
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'''Domoic acid''' ('''DA''') is a [[kainic acid]]-type [[neurotoxin]] that causes [[amnesic shellfish poisoning]] (ASP).<ref name = "Clayden_2005">{{cite journal | vauthors = Clayden J, Read B, Hebditch KR | title = Chemistry of domoic acid, isodomoic acids, and their analogues. | journal = Tetrahedron | date = 2005 | volume = 24 | issue = 61 | pages = 5713–24 | doi = 10.1016/j.tet.2005.04.003 }}</ref> 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, delirium and possibly death.<ref>{{cite web|title=Domoic Acid Toxicity|url=http://www.marinemammalcenter.org/science/top-research-projects/domoic-acid-toxicity.html|website=The Marine Mammal Center|access-date=2 April 2015}}</ref>

==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.<ref>{{Cite book |last=Beasley |first=Val Richard |title=Reference Module in Earth Systems and Environmental Sciences |date=2020 |publisher=Elsevier |isbn=9780124095489 |chapter=Harmful Algal Blooms (Phycotoxins)}}</ref>
Domoic acid was first isolated in 1959 from a species of red algae, ''[[Chondria (alga)|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.<ref>{{cite journal | vauthors = McCabe RM, Hickey BM, Kudela RM, Lefebvre KA, Adams NG, Bill BD, Gulland FM, Thomson RE, Cochlan WP, Trainer VL | title = An unprecedented coastwide toxic algal bloom linked to anomalous ocean conditions | journal = Geophysical Research Letters | volume = 43 | issue = 19 | pages = 10366–10376 | date = October 2016 | pmid = 27917011 | pmc = 5129552 | doi = 10.1002/2016GL070023 | bibcode = 2016GeoRL..4310366M }}</ref>

In 1961, seabirds attacked the [[Capitola, California|Capitola]] area in [[California]], and though it was never confirmed, it was later hypothesized that they were under the influence of domoic acid.<ref>{{cite web|title=DOMOIC ACID - A major concern to washington state's shellfish lovers|url=http://wdfw.wa.gov/fishing/shellfish/razorclams/domoic_acid.html|website=Washington Department of Fish and wildlife|access-date=12 April 2015|archive-url=https://web.archive.org/web/20131203063841/http://wdfw.wa.gov/fishing/shellfish/razorclams/domoic_acid.html|archive-date=3 December 2013|url-status=dead}}</ref>

In 1987, in [[Prince Edward Island]], Canada, there was a shellfish poisoning resulting in 3 deaths. [[Blue mussel]]s (''Mytilus edulis'') contaminated with domoic acid were blamed.<ref name = "Gilbert_Toxipedia">{{cite web|last1=Gilbert|first1=Steven|name-list-style=vanc|title=Domoic Acid|url=http://www.toxipedia.org/display/toxipedia/Domoic+Acid|website=Toxipedia|access-date=15 April 2015|archive-date=5 May 2015|archive-url=https://web.archive.org/web/20150505041007/http://www.toxipedia.org/display/toxipedia/Domoic+Acid|url-status=dead}}</ref>

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 [[California State Route 1|Pacific Coast Highway]].<ref>{{cite web|title=Possibly drunk pelican hits windshield|url=https://www.nbcnews.com/id/wbna13525699|work=NBC news|access-date=12 April 2015|date=2006-06-24}}</ref>

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, California|Pismo Beach]] on the Central [[California]] coast.<ref>{{cite web|title='It was just total fear': California teen describes being attacked by sea lion|url=https://abcnews.go.com/US/total-fear-california-teen-describes-attacked-sea-lion/story?id=63856931&cid=clicksource_4380645_null_twopack_hed|work=ABC News|access-date=21 June 2019}}</ref>

==Chemistry==

===General===

Domoic acid is a structural analog of [[kainic acid]], [[proline]], and endogenous excitatory neurotransmitter [[glutamate]].<ref>{{cite journal | vauthors = Cendes F, Andermann F, Carpenter S, Zatorre RJ, Cashman NR | title = Temporal lobe epilepsy caused by domoic acid intoxication: evidence for glutamate receptor-mediated excitotoxicity in humans | journal = Annals of Neurology | volume = 37 | issue = 1 | pages = 123–6 | date = January 1995 | pmid = 7818246 | doi = 10.1002/ana.410370125 | s2cid = 22318425 }}</ref> Ohfune and Tomita, who wanted to investigate its absolute stereochemistry, were the first and only to synthesize domoic acid in 1982.<ref name = "Clayden_2005" />

===Biosynthesis===

In 1999, using [[Carbon-13|<sup>13</sup>C]]- and [[Carbon-14|<sup>14</sup>C]]-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.<ref>{{cite journal | vauthors = Ramsey UP, Douglas DJ, Walter JA, Wright JL | title = Biosynthesis of domoic acid by the diatom Pseudo-nitzschia multiseries | journal = Natural Toxins | volume = 6 | issue = 3–4 | pages = 137–46 | date = 1999 | pmid = 10223629 | doi = 10.1002/(sici)1522-7189(199805/08)6:3/4<137::aid-nt28>3.0.co;2-l }}</ref>

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.<ref name=":0">{{cite journal | vauthors = Brunson JK, McKinnie SM, Chekan JR, McCrow JP, Miles ZD, Bertrand EM, Bielinski VA, Luhavaya H, Oborník M, Smith GJ, Hutchins DA, Allen AE, Moore BS | title = Biosynthesis of the neurotoxin domoic acid in a bloom-forming diatom | journal = Science | volume = 361 | issue = 6409 | pages = 1356–1358 | date = September 2018 | pmid = 30262498 | doi = 10.1126/science.aau0382 | pmc = 6276376 | bibcode = 2018Sci...361.1356B }}</ref> 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).[[File:Domoic_Acid_Biosynthesis.png|alt=|thumb|upright=4|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".<ref name=":0" />|center]]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 ===
[[File:Domoic Acid Synthesis.pdf|thumb|right|class=skin-invert-image|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.<ref name = "Clayden_2005" />|alt=]]
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.<ref name = "Clayden_2005" />

==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 [[amygdala|amygdaloid]] nucleus. It damages the neurons by activating [[AMPA receptor|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.<ref>{{cite journal | vauthors = Pulido OM | title = Domoic acid toxicologic pathology: a review | journal = Marine Drugs | volume = 6 | issue = 2 | pages = 180–219 | date = May 2008 | pmid = 18728725 | pmc = 2525487 | doi = 10.3390/md20080010 | doi-access = free }}</ref><ref name = "Smith–blog">{{cite web|last1=Smith|first1=Torrey|name-list-style=vanc|title=Toxin in seafood causes kidney damage in mice at levels considered safe for consumption|url=http://www.avantemedicalcenter.com/news-info/avante-blog/127-toxin-in-seafood-causes-kidney-damage-in-mice-at-levels-considered-safe-for-consumption.html|website=avante medical center|access-date=2015-04-30|archive-date=2019-02-14|archive-url=https://web.archive.org/web/20190214233343/https://www.avantemedicalcenter.com/news-info/avante-blog/127-toxin-in-seafood-causes-kidney-damage-in-mice-at-levels-considered-safe-for-consumption.html|url-status=dead}}</ref>

{| class="wikitable floatleft "
|+ Symptoms of domoic acid
|-
! Humans !! Animals
|-
| vomiting || head weaving
|-
| nausea || seizures
|-
| diarrhea and abdominal cramps<br>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 ||
|-
| colspan="2" |References for all, unless otherwise noted:<ref name = "Gilbert_Toxipedia" /> 
|}

==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&nbsp;mg/kg of body weight. In the 1987 domoic acid poisoning on Prince Edward Island concentrations ranging from 0.31 to 1.28&nbsp;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 LD<sub>50</sub> is 3.6&nbsp;mg/kg.<ref name = "Gilbert_Toxipedia" />

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.<ref name = "Smith–blog" />

{{clear left}}

==Diagnosis and prevention==
In order to be diagnosed and treated if poisoned, domoic acid must first be detected. Methods such as [[enzyme-linked immunosorbent assay|ELISA]] or probe development with [[polymerase chain reaction]] (PCR) may be used to detect the toxin or the organism producing this toxin.<ref>{{cite web|title=Detection and Analysis of Marine Biotoxins|url=http://www.nwfsc.noaa.gov/hab/research/nwfsc_research/detection_analysis/|website=Northwest fisheries science center|access-date=2015-04-30|archive-url=https://web.archive.org/web/20160304200452/http://www.nwfsc.noaa.gov/hab/research/nwfsc_research/detection_analysis/|archive-date=2016-03-04|url-status=dead}}</ref>

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.<ref>{{cite web|title=Domoic Acid - A Major Concern to Washington State's Shellfish Lovers|url=http://wdfw.wa.gov/fishing/shellfish/razorclams/domoic_acid.html|website=washington department of fish and wildlife|access-date=2012-04-08|archive-url=https://web.archive.org/web/20131203063841/http://wdfw.wa.gov/fishing/shellfish/razorclams/domoic_acid.html|archive-date=2013-12-03|url-status=dead}}</ref>

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&nbsp;mg/kg tissue. In addition, during processing shellfish, it is important to pay attention to environmental condition factors.<ref>{{cite journal | vauthors = Kumar KP, Kumar SP, Nair GA | title = Risk assessment of the amnesic shellfish poison, domoic acid, on animals and humans | journal = Journal of Environmental Biology | volume = 30 | issue = 3 | pages = 319–25 | date = May 2009 | pmid = 20120452 }}</ref>

==In popular culture==
On August 18, 1961, in [[Capitola, California|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 (film)|The Birds]]''.<ref>{{cite journal | vauthors = Bargu S, Silver MW, Ohman MD, Benitez-Nelson CR, Garrison DL |title=Mystery behind Hitchcock's birds |journal=Nature Geoscience |volume=5 |issue=1 |year=2011 |pages=2–3 |doi=10.1038/ngeo1360 |bibcode=2012NatGe...5....2B |s2cid=128391841 |url=https://escholarship.org/uc/item/4mj5d2pp }}</ref>

In the ''[[Elementary (TV series)|Elementary]]'' Season 1 Episode 13 "The Red Team", domoic acid was used as a poison to mimic [[Alzheimer's]].<ref>{{cite web |title=Elementary s01e13 Episode Script {{!}} SS |url=https://www.springfieldspringfield.co.uk/view_episode_scripts.php?tv-show=elementary&episode=s01e13 |website=Springfield! Springfield!}}</ref>

In the tv show “Bunk’d” domoic acid somehow combines with fog to create a chemical that causes people to lose memory or gain alter egos when inhaled.

== See also ==
* [[Canadian Reference Materials]]
* ''[[Pseudo-nitzschia]]''
* [[Quisqualic acid]]
* [[Brevetoxin]]
* [[Ciguatoxin]]
* [[Okadaic acid]]
* [[Saxitoxin]]
* [[Maitotoxin]]

== References ==
{{Reflist|30em}}

== External links ==
* {{cite web|url=http://www.inter.dfo-mpo.gc.ca/Gulf/DAPR |title=Domoic Acid and ''Pseudo-nitzschia'' References |publisher=[[Fisheries and Oceans Canada]] |url-status=dead |archive-url=https://web.archive.org/web/20131204023151/http://www.inter.dfo-mpo.gc.ca/Gulf/DAPR |archive-date=2013-12-04 }}
* {{cite web | url = http://www.issha.org/Welcome-to-ISSHA/Harmful-Algae-Links/Phycotoxins/Domoic-Acid-ASP | title = Amnesic Shellfish Poisoning, Domoic Acid, and ''Pseudo-nitzschia'' | publisher = International Society for the Study of Harmful Algae ISSHA | access-date = 2010-05-07 | archive-url = https://web.archive.org/web/20131203012507/http://www.issha.org/Welcome-to-ISSHA/Harmful-Algae-Links/Phycotoxins/Domoic-Acid-ASP | archive-date = 2013-12-03 | url-status = dead }}
* {{ cite web | url = http://www.inchem.org/documents/pims/animal/pim670.htm | title = Domoic acid | publisher = IPCS INCHEM }}
* {{cite web | url = http://wdfw.wa.gov/fishing/shellfish/razorclams/domoic_acid.html | title = Domoic Acid - A Major Concern to Washington State's Shellfish Lovers | publisher = Washington Department of Fish and Wildlife | access-date = 2012-04-08 | archive-url = https://web.archive.org/web/20131203063841/http://wdfw.wa.gov/fishing/shellfish/razorclams/domoic_acid.html | archive-date = 2013-12-03 | url-status = dead }}
* {{ cite web | url = http://www.marinemammalcenter.org/science/top-research-projects/domoic-acid-toxicity.html | title = Domoic Acid Toxicity}}

{{Ionotropic glutamate receptor modulators}}

{{DEFAULTSORT:Domoic Acid}}
[[Category:Marine neurotoxins]]
[[Category:Phycotoxins]]
[[Category:Secondary amino acids]]
[[Category:Pyrrolidines]]
[[Category:AMPA receptor agonists]]
[[Category:Kainate receptor agonists]]
[[Category:Chelating agents]]
[[Category:Tricarboxylic acids]]
[[Category:Conjugated dienes]]
[[Category:Toxic amino acids]]
[[Category:Excitotoxins]]
[[Category:Convulsants]]