Kalkitoxin

Kalkitoxin, a lipopeptide derived from the cyanobacterium Lyngbya majuscula, induces NMDA receptor mediated neuronal necrosis, blocks voltage-dependent sodium channels, and induces cellular hypoxia by inhibiting the electron transport chain (ETC) complex 1.

Sources

Kalkitoxin is an ichthyotoxin, derived from the cyanobacterium Lyngbya majuscula [1] which covers sections of the coral reef.[2] It typically forms mini-blooms[2] and produces several metabolites, such as kalkitoxin, curacin-A and antillatoxin.[1] Kalkitoxin has been found and purified near the coasts of Curaçao[1] and Puerto Rico.[3]

Chemistry

Kalkitoxine is a lipopeptide toxin[4] with a molecular weight of 366.604Da.[5] Its chemical formula is C21H38N2OS.[6] The kalkitoxin carbon chain contains two double bonds,[6] a ring system, which is in the natural form a 2,4-disubstituted thiazoline, and an additional carbonyl-group.[6] These four different groups are unsaturated, which causes kalkitoxin to have four degrees of unsaturation:[6] double bonds can be broken and new functional groups can be added to the molecule. In kalkitoxin, there is one thiazoline group and four methylgroups. These groups are carbon atoms, attached to four different types of atoms. This causes kalkitoxin to have a total of five asymmetric carbon centers in kalkitoxin.[7] The four methylgroups, the different stereochemistry, and a N-methylgroup all contribute to the toxicity of kalkitoxin.[7]

Targets

Kalkitoxin may activate the NMDA receptor.[1] It also blocks the voltage-gated sodium channel[8] and the electron transport chain (ETC) complex 1.[8] It remains unknown how exactly kalkitoxin binds to the voltage-gated sodium channel. Neurotoxin sit 1 and 2 have been ruled out as possible binding sites, whereas neurotoxin site 7 is suggested as binding site for kalkitoxin.[4] This is probable, because there is inhibition of the channel by kalkitoxin when deltamethrin, which has positive allosteric effects, is present.[8] This could be because molecular determinants for binding are similar in kalkitoxin and deltamethrin.[8]

Mode of Action

Kalkitoxin induces delayed neuronal necrosis in cerebellar granule cells of the rat.[1] This neuronal necrosis proved to be NMDA-receptor mediated.[1] These receptors are normally activated by glutamate and other excitotoxic compounds and can induce neuronal necrosis.[1] It is not yet known if the toxin induces necrosis directly or via the release of excitotoxic compounds.[1]

Secondly, Kalkitoxin blocks voltage-gated sodium channels, thereby inhibiting Ca2+ release that normally occurs when the voltage-gated sodium channel is activated, in a concentration dependent matter.[8] Calcium release has been shown to induce lactate dehydrogenase (LDH) production.[8] The amount of LDH is a measure for neuronal cell death.[8] In the presence of kalkitoxin there is also a concentration-dependent inhibition of neuronal cell death and LDH production (9). The mechanism behind this inhibition is still unknown.[8]

Thirdly, kalkitoxin blocks the electron transport chain (ETC) complex 1,[2] one of the protein complexes involved in mitochondrial respiration.[2] By blocking the ETC complex 1, kalkitoxin potently inhibits hypoxia-inducible factor-1 (HIF-1) activation.[2] HIF-1 is a transcription factor, which enhances the expression of genes that increase oxygen availability, as well as genes that decrease oxygen consumption.[2] Inhibition of HIF-1, which is one of the main effects of kalkitoxin, thus induces cellular hypoxia.

Toxicity

Kalkitoxin is ichthyotoxic to goldfish (Carassius auratus, LC50: 700nM) and to aquatic crustacean brine shrimp (Artemia salina, LC50: 150-180nM [7]).[9] Kalkitoxin also has been shown to have delayed neurotoxic effects on cerebellar granule cells of the rat (LC50: 3,86nM).[2]

References

  1. 1 2 3 4 5 6 7 8 Berman; et al. (1999). "Antillatoxin and kalkitoxin, ichthyotoxins from the tropical cyanobacterium Lyngbya majuscula, induce distinct temporal patterns of NMDA receptor-mediated neurotoxicity". Toxicon. PMID 10482399.
  2. 1 2 3 4 5 6 7 Morgan; et al. (2015). "Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling and blocks mitochondrial electron transport in tumor cells". Marine Drugs. 13. PMID 25803180.
  3. ↑ Nogle and Gerwick (2003). "Diverse Secondary Metabolites from a Puerto Rican Collection of Lyngbya Majuscula". Journal of Natural Products. 66. PMID 12608852.
  4. 1 2 Wu, M. (1997). Novel bioactive secondary metabolites from the marine cyanobacterium Lyngbya majuscule, Thesis (M.S.). Oregon State University – via https://www.researchgate.net/publication/33818310_Novel_bioactive_secondary_metabolites_from_the_marine_cyanobacterium_Lyngbya_majuscula.
  5. ↑ Royal Society of Chemistry 2015. "ChemSpider Kalkitoxin".
  6. 1 2 3 4 Wu; et al. (2000). "Structure, Synthesis, and Biological Properties of Kalkitoxin, a Novel Neurotoxin from the Marine Cyanobacterium Lyngbya majuscule". Journal of the American Society. doi:10.1021/ja005526y.
  7. 1 2 3 Umezawa; et al. (2011). "Synthesis and Biological Activity of Kalkitoxin and its Analogues". Journal of Organic Chemistry. 77. PMID 22111947.
  8. 1 2 3 4 5 6 7 8 LePage; et al. (2005). "The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons". Toxicology Letters. 158. PMID 16039402.
  9. ↑ Sarma, T.A. (2012). Handbook of Cyanobacteria. CRC Press. p. 539. ISBN 9781578088003.
This article is issued from Wikipedia - version of the 10/15/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.