Okadaic acid

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Okadaic acid
Okadaic acid.svg
Names
Preferred IUPAC name
(2R)-2-Hydroxy-2-{[(2S,5R,6R,8S)-5-hydroxy-8-{(2R,3E)-4-[(2R,4′aR,6′S,8′R,8′aS)-8′-hydroxy-6′-{(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl}-7′-methylidenehexahydro-3′H-spiro[oxolane-2,2′-pyrano[3,2-b]pyran]-5-yl]but-3-en-2-yl}-10-methyl-1,7-dioxaspiro[5.5]undec-10-en-2-yl]methyl}propanoic acid
Other names
9,10-Deepithio-9,10-didehydroacanthifolicin
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.116.145 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH Acid Okadaic Acid
PubChem CID
UNII
  • InChI=1S/C44H68O13/c1-25-21-34(55-44(23-25)35(46)12-11-31(54-44)24-41(6,50)40(48)49)26(2)9-10-30-14-18-43(53-30)19-15-33-39(57-43)36(47)29(5)38(52-33)32(45)22-28(4)37-27(3)13-17-42(56-37)16-7-8-20-51-42/h9-10,23,26-28,30-39,45-47,50H,5,7-8,11-22,24H2,1-4,6H3,(H,48,49)/b10-9+/t26-,27-,28+,30+,31+,32+,33-,34+,35-,36-,37+,38+,39-,41-,42+,43-,44-/m1/s1 Yes check.svgY
    Key: QNDVLZJODHBUFM-WFXQOWMNSA-N Yes check.svgY
  • InChI=1/C44H68O13/c1-25-21-34(55-44(23-25)35(46)12-11-31(54-44)24-41(6,50)40(48)49)26(2)9-10-30-14-18-43(53-30)19-15-33-39(57-43)36(47)29(5)38(52-33)32(45)22-28(4)37-27(3)13-17-42(56-37)16-7-8-20-51-42/h9-10,23,26-28,30-39,45-47,50H,5,7-8,11-22,24H2,1-4,6H3,(H,48,49)/b10-9+/t26-,27-,28+,30+,31+,32+,33-,34+,35-,36-,37+,38+,39-,41-,42+,43-,44-/m1/s1
    Key: QNDVLZJODHBUFM-WFXQOWMNBB
  • InChI=1S/C44H68O13/c1-25-21-34(55-44(23-25)35(46)12-11-31(54-44)24-41(6,50)40(48)49)26(2)9-10-30-14-18-43(53-30)19-15-33-39(57-43)36(47)29(5)38(52-33)32(45)22-28(4)37-27(3)13-17-42(56-37)16-7-8-20-51-42/h9-10,23,26-28,30-39,45-47,50H,5,7-8,11-22,24H2,1-4,6H3,(H,48,49)/b10-9+/t26-,27-,28+,30+,31+,32+,33-,34+,35-,36-,37+,38+,39-,41-,42+,43-,44-/m1/s1
    Key: QNDVLZJODHBUFM-WFXQOWMNSA-N
  • O=C(O)[C@@](O)(C)C[C@H]7O[C@]/1(O[C@@H](CC(=C\1)\C)[C@@H](/C=C/[C@@H]6O[C@@]3(O[C@H]2[C@H](O)/C(=C)[C@H](O[C@@H]2CC3)[C@@H](O)C[C@H](C)[C@H]5O[C@]4(OCCCC4)CC[C@H]5C)CC6)C)[C@H](O)CC7
Properties
C44H68O13
Molar mass 805.015 g·mol−1
Melting point 164-166 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Okadaic acid, C44H68O13, is a toxin produced by several species of dinoflagellates, and is known to accumulate in both marine sponges and shellfish. [1] One of the primary causes of diarrhetic shellfish poisoning, okadaic acid is a potent inhibitor of specific protein phosphatases and is known to have a variety of negative effects on cells. [2] [3] A polyketide, polyether derivative of a C38 fatty acid, okadaic acid and other members of its family have shined light upon many biological processes both with respect to dinoflagellete polyketide synthesis as well as the role of protein phosphatases in cell growth. [4] [5] [6]

Contents

History

As early as 1961, reports of gastrointestinal disorders following the consumption of cooked mussels appeared in both the Netherlands and Los Lagos. Attempts were made to determine the source of the symptoms, however they failed to elucidate the true culprit, instead implicating a species of microplanctonic dinoflagellates. [1] In the summers of the late 1970s, a series of food poisoning outbreaks in Japan lead to the discovery of a new type of shellfish poisoning. Named for the most prominent symptoms, the new Diarrhetic Shellfish Poisoning (DSP) only affected the northern portion of Honshu during 1976, however by 1977 large cities such as Tokyo and Yokohama were affected. Research into the shellfish consumed in the affected regions showed that a fat-soluble toxin was responsible for the 164 documented cases, and this toxin was traced to mussels and scallops harvested in the Miyagi prefecture. [7] In northeastern Japan, a legend had existed that during the season of paulownia flowers, shellfish can be poisonous. Studies following this outbreak showed that toxicity of these mussels and scallops appeared and increased during the months of June and July, and all but disappeared between August and October. [7] [8]

Elsewhere in Japan, in 1975 Fujisawa pharmaceutical company observed that the extract of a black sponge, Halichondria okadai , was a potent cytotoxin, and was dubbed Halichondrine-A. In 1981, the structure of one such toxin, okadaic acid, was determined after it was extracted from both the black sponge in Japan, Halichondria okadai, for which it was named, and a sponge in the Florida Keys, Halichondria melanodocia. Okadaic acid sparked research both for its cytotoxic feature and for being the first reported marine ionophore. [9] [10]

One of the toxic culprits of DSP, dinophysistoxin-1 (DTX-1), named for one of the organisms implicated in its production, Dinophysis fortii, was compared to and shown to be very chemically similar to okadaic acid several years later, and okadaic acid itself was implicated in DSP around the same time. [8] Since its initial discovery, reports of DSP have spread throughout the world, and are especially concentrated in Japan, South America and Europe. [3] [11]

Synthesis

Derivatives

Okadaic acid (OA) and its derivatives, the dinophysistoxins (DTX), are members of a group of molecules called polyketides. The complex structure of these molecules include multiple spiroketals, along with fused ether rings. [1] [5]

Structures of Okadaic Acid and the Dinophysistoxins OAandDTXStructures.png
Structures of Okadaic Acid and the Dinophysistoxins

Biosynthesis

Being polyketides, the okadaic acid family of molecules are synthesized by dinoflagellates via polyketide synthase (PKS). However unlike the majority of polyketides, the dinoflagellate group of polyketides undergo a variety of unusual modifications. Okadaic acid and its derivatives are some of the most well studied of these polyketides, and research on these molecules via isotopic labeling has helped to elucidate some of those modifications. [6] [12]

Okadaic acid is formed from a starter unit of glycolate, found at carbons 37 and 38, and all subsequent carbons in the chain are derived from acetate. Because polyketide synthesis is similar to fatty acid synthesis, during chain extension the molecule may undergo reduction of the ketone, dehydration, and reduction of the olefin. Failure to perform one of more of these three steps, combined with several unusual reactions is what allows for the formation of the functionality of okadaic acid. Carbon deletion and addition at the alpha and beta position comprise the other transformations present in the okadaic acid biosynthesis. [6]

Carbon deletion occurs by way of a Favorskii rearrangement and subsequent decarboxylation. Attack of a ketone in the growing chain by enzyme-bound acetates, and subsequent decarboxylation/dehydration results in an olefin replacing the ketone, in both alpha and beta alkylation. After this the olefin can isomerize to more thermodynamically stable positions, or can be activated for cyclizations, in order to produce the natural product. [6]

Laboratory syntheses

Isobe's Synthesis of Okadaic Acid. IsobeOASynthesis.png
Isobe's Synthesis of Okadaic Acid.

To date, several studies have been performed toward the synthesis of okadaic acid and its derivatives. 3 total syntheses of okadaic acid have been achieved, along with many more formal syntheses and several total syntheses of the other dinophysistoxins. The first total synthesis of okadaic acid was completed in 1986 by Isobe et al., just 5 years after the molecule's structure was elucidated. The next two were completed in 1997 and 1998 by the Forsyth and Ley groups respectively. [5] [13] [14] [15]

In Isobe's synthesis, the molecule was broken into 3 pieces, along the C14-C15 bonds, and the C27-C28 bonds. This formed fragments A, B, and C, which were all synthesized separately, after which the B and C fragments were combined, and then combined with the A fragment. This synthesis contained 106 steps, with a longest linear sequence of 54 steps. The precursors to all three fragments were all glucose derivatives obtained from the chiral pool. Spiroketals were obtained from precursor ketone diols, and were therefore formed thermally in acid. [5] [13] [16]

Forsyth's Synthesis of Okadaic Acid. ForsythOASynthesis.png
Forsyth's Synthesis of Okadaic Acid.

Similar to Isobe's synthesis, the Forsyth synthesis sought to reduce the number of steps, and to increase potential for designing analogues late in the synthesis. To do this, Forsyth et al. designed the synthesis to allow for structural changes and installation of important functional groups before large pieces were joined. Their resulting synthesis was 3% yielding, with 26 steps in the longest linear sequence. As above, spiroketalization was performed thermodynamically with introduction of acid. [5] [14]

Ley's Synthesis of Okadaic Acid. LeyOASynthesis.png
Ley's Synthesis of Okadaic Acid.

Ley's synthesis of okadaic acid is most unlike its predecessors, although it still contains similar motifs. Like the others, this synthesis divided okadaic acid into three components along the acyclic segments. However, designed to display new techniques developed in their group, Ley's synthesis included forming the spiroketals using (diphenylphosphineoxide)-tetrahydrofuran and (phenylsulfonyl)-tetrahydropyrans, allowing for more mild conditions. Similar to those above, a portion of the stereochemistry in the molecule was set by starting materials obtained from the chiral pool, in this case mannose. [5] [15]

Biology

Mechanism of action

Okadaic acid (OA) and its relatives are known to strongly inhibit protein phosphatases, specifically serine/threonine phosphatases. [5] Furthermore, of the 4 such phosphatases, okadaic acid and its relatives specifically target protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), at the exclusion of the other two, with dissociation constants for the two proteins of 150 nM and 30 pM respectively. [16] Because of this, this class of molecules has been used to study the action of these phosphatases in cells. [16] [17] Once OA binds to the phosphatase protein(s), it results in hyperphosphorylation of specific proteins within the afflicted cell, which in turn reduces control over sodium secretion and solute permeability of the cell. [18] Affinity between okadaic acid and its derivatives and PP2A has been tested, and it was shown that the only derivative with a lower dissociation constant, and therefore higher affinity, was DTX1, which has been shown to be 1.6 times stronger. [3] [16] Furthermore, for the purpose of determining the toxicity of mixtures of different okadaic acid derivatives, inhibitory equivalency factors for the relatives of okadaic acid have been studied. In wild type PP2A, the inhibitory equivalency relative to okadaic acid were 0.9 for DTX-1 and 0.6 for DTX-2. [18]

Toxicology

The main route of exposure to DSP from okadaic acid and its relatives is through the consumption of shellfish. It was initially shown that the toxic agents responsible for DSP tend to be most concentrated in the hepatopancreas, followed by the gills for certain shellfish. [1] [7] [19] The symptoms for diarrhetic shellfish poisoning include intense diarrhea and severe abdominal pains, and rarely nausea and vomiting, and they tend to occur anytime between 30 minutes and at most 12 hours after consuming toxic shellfish. [7] [11] It has been estimated that it takes roughly 40 μg of okadaic acid to trigger diarrhea in adult humans. [3]

Medical uses

Because of its inhibitory effects in phosphatases, okadaic acid has shown promise in the world of medicine for numerous potential uses. During its initial discovery, okadaic acid, specifically the crude source extract, showed potent inhibition of cancer cells, and so initial interest in the family of molecules tended to center around that feature. [8] [9] However, it was shown that the more cytotoxic component of H. okadai was actually a separate family of compounds, the Halichondrines, and as such research into the cytotoxicity of okadaic acid decreased. [5] However, the unique function of okadaic acid upon cells maintained biological interest in the molecule. Okadaic acid has been shown to have neurotoxic, immunotoxic, and embryotoxic effects. [3] [20] Furthermore, in two-stage carcinogenesis of mouse skin, the molecule and its relatives have been shown to have tumor promoting effects. Because of this, the effects of okadaic acid on Alzheimer's, AIDS, diabetes, and other human diseases have been studied. [3] [4] [20]

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".

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Tetrodotoxin</span> Neurotoxin

Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals. It is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas, Pseudomonas, and Vibrio as well as other species found in symbiotic relationships with animals and plants.

<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">Palytoxin</span> Chemical compound

Palytoxin, PTX or PLTX is an intense vasoconstrictor, and is considered to be one of the most poisonous non-protein substances known, second only to maitotoxin in terms of toxicity in mice.

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

Maitotoxin (MTX) is an extremely potent biotoxin produced by Gambierdiscus toxicus, a dinoflagellate species. Maitotoxin has been shown to be more than one hundred thousand times as potent as VX nerve agent. Maitotoxin is so potent that it has been demonstrated that an intraperitoneal injection of 130 ng/kg was lethal in mice. Maitotoxin was named from the ciguateric fish Ctenochaetus striatus—called "maito" in Tahiti—from which maitotoxin was isolated for the first time. It was later shown that maitotoxin is actually produced by the dinoflagellate Gambierdiscus toxicus.

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

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

Nodularins are potent toxins produced by the cyanobacterium Nodularia spumigena, among others. This aquatic, photosynthetic cyanobacterium forms visible colonies that present as algal blooms in brackish water bodies throughout the world. The late summer blooms of Nodularia spumigena are among the largest cyanobacterial mass occurrences in the world. Cyanobacteria are composed of many toxic substances, most notably of microcystins and nodularins: the two are not easily differentiated. A significant homology of structure and function exists between the two, and microcystins have been studied in greater detail. Because of this, facts from microcystins are often extended to nodularins.

<span class="mw-page-title-main">Halichondrin B</span> Chemical compound

Halichondrin B is a polyether macrolide originally isolated from the marine sponge Halichondria okadai by Hirata and Uemura in 1986. In the same report, these authors also reported the exquisite anticancer activity of halichondrin B against murine cancer cells both in culture and in in vivo studies. Halichondrin B was highly prioritized for development as a novel anticancer therapeutic by the United States National Cancer Institute and, in 1991, was the original test case for identification of mechanism of action by NCI's then-brand-new "60-cell line screen"

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

Yessotoxins are a group of lipophilic, sulfur bearing polyether toxins that are related to ciguatoxins. They are produced by a variety of dinoflagellates, most notably Lingulodinium polyedrum and Gonyaulax spinifera.

<span class="mw-page-title-main">Microcystin-LR</span> Chemical compound

Microcystin-LR (MC-LR) is a toxin produced by cyanobacteria. It is the most toxic of the microcystins.

<span class="mw-page-title-main">Protein phosphatase 1</span>

Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen metabolism, muscle contraction, cell progression, neuronal activities, splicing of RNA, mitosis, cell division, apoptosis, protein synthesis, and regulation of membrane receptors and channels.

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

Azaspiracids (AZA) are a group of polycyclic ether marine algal toxins produced by the small dinoflagellate Azadinium spinosum that can accumulate in shellfish and thereby cause illness in humans.

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.

Canadian Reference Materials (CRM) are certified reference materials of high-quality and reliability produced by the National Metrology Institute of Canada – the National Research Council Canada. The NRC Certified Reference Materials program is operated by the Measurement Science and Standards portfolio and provides CRMs for environmental, biotoxin, food, nutritional supplement, and stable isotope analysis. The program was established in 1976 to produce CRMs for inorganic and organic marine environmental analysis and remains internationally recognized producer of CRMs.

<i>Dinophysis acuminata</i> Species of dinoflagellate

Dinophysis acuminata is a marine plankton species of dinoflagellates that is found in coastal waters of the north Atlantic and Pacific oceans. The genus Dinophysis includes both phototrophic and heterotrophic species. D. acuminata is one of several phototrophic species of Dinophysis classed as toxic, as they produce okadaic acid which can cause diarrhetic shellfish poisoning (DSP). Okadiac acid is taken up by shellfish and has been found in the soft tissue of mussels and the liver of flounder species. When contaminated animals are consumed, they cause severe diarrhoea. D. acuminata blooms are constant threat to and indication of diarrhoeatic shellfish poisoning outbreaks.

<i>Dinophysis acuta</i> Species of dinoflagellate

Dinophysis acuta is a species of flagellated planktons belonging to the genus Dinophysis. It is one of the few unusual photosynthetic protists that acquire plastids from algae by endosymbiosis. By forming massive blooms, particularly in late summer and spring, it causes red tides. It produces toxic substances and the red tides cause widespread infection of seafood, particularly crabs and mussels. When infected animals are consumed, severe diarrhoea occurs. The clinical symptom is called diarrhetic shellfish poisoning. The main chemical toxins were identified in 2006 as okadaic acid and pectenotoxins. They can produce non-fatal or fatal amounts of toxins in their predators, which can become toxic to humans.

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

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 along with a molecule that is also referred to as saxitoxin (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 contaminated by toxic algae can cause a human illness called paralytic shellfish poisoning (PSP).

Fostriecin is a type I polyketide synthase (PKS) derived natural product, originally isolated from the soil bacterium Streptomyces pulveraceus. It belongs to a class of natural products which characteristically contain a phosphate ester, an α,β-unsaturated lactam and a conjugated linear diene or triene chain produced by Streptomyces. This class includes structurally related compounds cytostatin and phoslactomycin. Fostriecin is a known potent and selective inhibitor of protein serine/threonine phosphatases, as well as DNA topoisomerase II. Due to its activity against protein phosphatases PP2A and PP4 which play a vital role in cell growth, cell division, and signal transduction, fostriecin was looked into for its antitumor activity in vivo and showed in vitro activity against leukemia, lung cancer, breast cancer, and ovarian cancer. This activity is thought to be due to PP2A's assumed role in regulating apoptosis of cells by activating cytotoxic T-lymphocytes and natural killer cells involved in tumor surveillance, along with human immunodeficiency virus-1 (HIV-1) transcription and replication.

References

  1. 1 2 3 4 Reguera, B.; Riobo, P.; Rodriguez, F.; Diaz, P. A.; Pizarro, G.; Paz, B.; Franco, J. M.; Blanco, J. (January 2014). "Dinophysis Toxins: Causative Organisms, Distribution and Fate in Shellfish". Mar. Drugs. 12 (1): 394–461. doi: 10.3390/md12010394 . PMC   3917280 . PMID   24447996.
  2. ↑ Holmes, C. F. B.; Luu, H. A.; Carrier, F.; Schmitz, F. J. (1990). "Inhibition of protein phosphatases-1 and -2A with acanthifolicin: Comparison with diarrhetic shellfish toxins and identification of a region on okadaic acid important for phosphatase inhibition". FEBS Lett. 270 (1–2): 216–218. Bibcode:1990FEBSL.270..216H. doi: 10.1016/0014-5793(90)81271-O . PMID   2171991.
  3. 1 2 3 4 5 6 Valdiglesias, V.; Prego-Faraldo, M. V.; Pasaro, E.; Mendez, J; Laffon, B (2013). "Okadaic Acid: More than a Diarrheic Toxin". Mar. Drugs. 11 (11): 4328–4349. doi: 10.3390/md11114328 . PMC   3853731 . PMID   24184795.
  4. 1 2 Garcia, A.; Cayla, X.; Guergnon, J.; Dessauge, F.; Hospital, V.; Rebollo, M. P.; Fleischer, A.; Rebollo, A. (2003). "Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis". Biochimie. 85 (8): 721–726. doi:10.1016/j.biochi.2003.09.004. PMID   14585537.
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  9. 1 2 Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Vanengen, D.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. (1981). "Okadaic acid, a cytotoxic polyether from two marine sponges of the genus Halichondria". J. Am. Chem. Soc. 103 (9): 2469–2471. doi:10.1021/ja00399a082.
  10. ↑ Shibata, S.; Ishida, Y.; Kitano, H.; Ohizumi, Y.; Habon, J.; Tsukitani, Y.; Kikuchi, H. (1982). "Contractile effects of okadaic acid, a novel ionophore-like substance from black sponge, on isolated smooth muscles under the condition of Ca deficiency". J. Pharmacol. Exp. Ther. 223 (1): 135–143. PMID   6214623.
  11. 1 2 Scoging, A.; Bahl, M. (1998). "Diarrhetic shellfish poisoning in the UK". The Lancet. 352 (9122): 117. doi:10.1016/S0140-6736(98)85023-X. PMID   9672285. S2CID   35211241.
  12. ↑ Weissman, K. J. (2009). "Chapter 1 Introduction to Polyketide Biosynthesis". Complex Enzymes in Microbial Natural Product Biosynthesis, Part B: Polyketides, Aminocoumarins and Carbohydrates. Methods in Enzymology. Vol. 459. pp. 3–16. doi:10.1016/S0076-6879(09)04601-1. ISBN   9780123745910. PMID   19362633.
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  14. 1 2 Forsyth, C. J.; Sabes, S. F.; Urbanek, R. A. (1997). "An Efficient Total Synthesis of Okadaic Acid". J. Am. Chem. Soc. 119 (35): 8381–8382. doi:10.1021/ja9715206.
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  16. 1 2 3 4 Takai, A.; Murata, M.; Torigoe, K.; Isobe, M.; Mieskes, G.; Yasumoto, T. (1992). "Inhibitory effect of okadaic acid derivatives on protein phosphatases. A study on structure-affinity relationship". Biochem. J. 284 (2): 539–544. doi:10.1042/bj2840539. PMC   1132671 . PMID   1318034.
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