Pinnatoxin
From Wikipedia, the free encyclopedia
Pinnatoxins are paralytic chemical compounds that inhibit neuronal and muscle-type nicotinic acetylcholine receptors. Although first discovered in shellfish, they are produced by the Peridiniacean dinoflagellate Vulcanodinium rugosum. Eight subtypes, designated pinnatoxin A-H, have been described.
Pinnatoxins are neurotoxins named after the genus Pinna, a group of bivalve molluscs, in reference to their original isolation from members of the genus Pinna attenuata[2][a] and later Pinna muricata.[3] The causative organism producing the toxin was later identified as the dinoflagellate Vulcanodinium rugosum.[4] The presence of the toxin has been identified in various locations, including the Pacific Ocean,[5][6] the Persian Gulf,[7] the Mediterranean Sea,[8] waters near Canada,[9] Scandinavia,[5] and South China,[10] and in water samples in Ireland.[11]
Chemistry
Pinnatoxins are part of the cyclic imine group of marine toxins. This group currently consists of pinnatoxins, pteriatoxins, spirolides, gymnodimines, spiro-prorocentimine and portimine. Eight different types of pinnatoxins have been described, named pinnatoxin A to H.[12][13][14][15][16]
All the pinnatoxins contain several key structural elements. The structure of pinnatoxin is composed of a cyclic imine (A ring) spirolinked to a cyclohexene ring (G ring), a dispiro 6,5,6 tricyclic ketal at C12-C23 (rings B, C, D), a bridged bicyclic ketal at C25-C30 (rings E, F) and a 27-membered macrocyclic ring spanning C5-C31.[12][13][14][15][16]
| Toxin | Molecular formula | Molecular weight (Da) | 2D structure |
|---|---|---|---|
| Pinnatoxin A | C41H61NO9 | 712.4444 |  |
| Pinnatoxin B, C | C42H64N2O9 | 741.4707 |  |
| Pinnatoxin D | C45H67NO10 | 782.4845 |  |
| Pinnatoxin E | C45H69NO10 | 784.5008 |  |
| Pinnatoxin F | C45H67NO9 | 766.4889 |  |
| Pinnatoxin G | C42H63NO7 | 694.4683 |  |
| Pinnatoxin H | C43H65NO7 | 708.4834 |  |
Table: molecular formula and molecular weight of pinnatoxins[12][13][14][15][16]
Target
Pinnatoxin A, G, E and F display a high-affinity antagonism for the neuronal α7 and muscle α12βϒδ nicotine acetylcholine receptors (nAChRs).[17][18][19][20] The affinity of pinnatoxins for nAChR subtypes is the result of a selectivity mechanism: the bulky bridged EF-ketal ring, specific for pinnatoxins, is able to interact with the sequence-variable loop F of the nAChRs.[17]
The inhibitory potency of pinnatoxin A depends on the nAChR subtype. It has the following ranking in selectivity: α7> α12βϒδ>α4β2. Pinnatoxin A has a 300-fold greater potency toward the α7 than to the α4β2 nAChR. Furthermore, the blocking of α7 appears to be irreversible.[17]
Pinnatoxin G shows no selectivity between the two neuronal subtypes α7 en α4β2 nAChRs. In contrast, pinnatoxin G interacts with 25-fold higher affinity than pinnatoxin A on the muscle-type nAChR. So the selectivity rank ordering of pinnatoxin G is α12βϒδ> α7 > α3β2 α4β2. Pinnatoxin E and F have the same order of selectivity for these receptors, although they differ in their potency. The rank order of potency at all receptors is F>G>E.[17][18][19]