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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.
Nodularin-R is the predominant toxin variant, though 10 variants of nodularin have been discovered to date. Nodularins are cyclic nonribosomal pentapeptides and contain several unusual non-proteinogenic amino acids such as N-methyl-didehydroaminobutyric acid and the β-amino acid ADDA. These compounds are relatively stable compounds: light, temperature, and microwaves do little to degrade the compounds.
Nodularins are often attributed to gastroenteritis, allergic irritation reactions, and liver diseases. Nodularin-R is most notorious as a potent hepatotoxin that may cause serious damage to the liver of humans and other animals. The WHO drinking water concentration limit for nodularins (extended from microcystins-LR) is 1.5 ug /L.
The basic framework for nodularin structure is 1- Z2-Adda3-D-γ-Glu4-5, where Z is a variable amino acid; the systematic name "nodularin- Z" (NOD- Z in short) is then assigned based on the one letter code (if available; longer code otherwise) of the amino acid. For the common NOD-R, the Z amino acid is arginine.
At the molecular level and in further detail, nodularin is processed in a complex manner to induce toxic effects. During digestion, nodularins diffuse from small intestine into liver due to active uptake by an unspecific organic anion transporter in the bile acid carrier transport system. This transporter is expressed in the gastrointestinal tract, kidney, brain, and liver. Once in the liver, nodularin inhibits three key enzymes, specifically the catalytic units of serine/threonine protein phosphatases: protein phosphatase 1 (PP-1) and protein phosphatase 2A. (PP-2A), and protein phosphatase 3 (PP-3). These enzymes act by removing the phosphate from a protein, inhibiting the function of the protein.
An initial noncovalent interaction involving the ADDA side chain (specifically where ADDA has a 6E double bond) of the nodularin and a free D-glutamyl carboxyl group off a cyclic structure of the phosphatase is the source of toxicity. The ADDA group blocks enzyme (phosphatase) activity by interacting with hydrophobic groove and obstructing substrate access to active site cleft. The toxin-phosphatase bond interactions (nodularin-PP-1, nodularin-PP-2A) are extremely strong. This leads to inhibition of the enzyme activity. Of note, nodularins differ from microcystins here: nodularins bind noncovalently to protein phosphatases while microcystins bind covalently.
A further interaction involves a Michael-addition covalent linkage of electrophilic α, β unsaturated carbonyl of a methyldehydroalanine residue on the nodularin to a thiol of cysteine 273 on PP-1. Though the covalent bond in step 2 is not essential for inhibition of enzyme activity, it does help mediate activity. Without this covalent bond, there is over a 10-fold reduction of nodularin affinity for the phosphatase. The inhibition of the protein phosphatases results in increased phosphorylation of cytoskeletal proteins and cytoskeletal associated proteins. The hyperphosphorylation of intermediate filaments of the cell, specifically of cytokeratin 8 and cytokeratin 18, is the main cause for protein imbalance. The protein imbalance stimulates redistribution and rearrangement of these proteins, which changes the whole cell morphology and membrane integrity. More specifically, this redistribution leads to collapse of actin microfilaments in the hepatocyte cytoskeleton and dislocation of a-actinin and Talin protein. Contact with neighboring cells is reduced and sinusoidal capillaries lose stability which rapidly leads to intrahepatic hemorrhage and often results in serious liver malfunction or death.
Considered from a public health and epidemiologic standpoint, there is a correlation of primary liver cancer in areas of China with nodularins and microcystins in the water of ponds, ditches, rivers, and shallow wells.
Experiments in rats, where animals were exposed to non-lethal doses of nodularin, provided evidence of its carcinogenicity via tumor-initiating and tumor promoting activity. This is achieved by the inhibition of PP-1 and PP-2A. Nodularins have been implicated in the expression of the oncogenes and tumor suppressor genes tumor necrosis factor-alpha, c-jun, jun-B, jun-D, c-fos, fos-B and fra-1 gene expression. More data is needed to have a better understanding of the carcinogenicity of nodularins.
Nodularins typically affect aquatic life such as fish and plants. However, in certain cases, nodularins have been cited in the deaths of dogs, sheep, and humans (dawson et al.). Nodularin poisoning is not very prevalent in humans: very few cases have been reported and confirmed as nodularin poisoning.
Research has indicated that treating during and after with melatonin (dose: 15 mg/kg of body weight) may have protective functions against oxidative stress and damage induced by nodularins.
Safety guidelines can be implemented to reducing risk, specifically involving the cleanliness standards of drinking water. Microorganisms have been proven effective in the biodegradation and removal of nodularins, which could be useful in controlling cyanobacterial blooms in public water supplies. Protective clothing and physically avoiding areas of visible cyanobacterial blooms help reduce accidental exposures.
Nodularins may also be produced by other cyanobacteria. Some strains of Nostoc living in symbiosis with plants produce nodularin; other strains produce microcystin. It was debated which class of compounds were the original hepatotoxin: recent authors argue for nodularin having evolved from the microcystin synthesis machinery, while some older articles support the opposite.
A nodularin found in the marine sponge Theonella swinhoei, nodularin-V in systemaic nomenclature, is better known as . It is unclear how the sponge produces this chemical, with speculation that it may have come from a cyanobacterial symbioant.
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