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.

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

Kalkitoxin is a lipopeptide toxin with a molecular weight of 366.604Da. Its chemical formula is C₂₁H₃₈N₂OS. The structure contains two double bonds, a 2,4-disubstituted thiazoline ring system, and an additional carbonyl-group. These four groups each provide a degree of unsaturation, which causes kalkitoxin to have four degrees of unsaturation. The structure contains 5 chiral centers, one of which is due to a substituent of the thiazoline ring, and the other four are due to methine groups along the aliphatic carbon chain, which are tertiary carbon atoms bearing three single carbon bonds and one hydrogen. The four methyl groups (each at a methine chiral center), the structure’s overall stereochemistry, and the N-methyl group all contribute to the toxicity of kalkitoxin.

The structure of kalkitoxin was first determined by characterizing six partial structures which were subsequently connected to yield the total structure. This investigation was largely carried out through various NMR experiments. Structure (a) is a sec-butyl group, indicated by characteristic deshielding of its central methine group due to the adjacent carbonyl. Structure (b) contains this carbonyl group, and an adjacent tertiary methylated nitrogen atom, constituting a tertiary amide group. Since this is a tertiary amide, it exists in a cis/trans mixture, which underlies the two conformations of Kalkitoxin. Structure (c) is a string of two methylene groups, then a methine group bearing a high-field methyl group. The next two groups identified (d,e) are identical and opposing strings of CH2-CH-CH3, however the left grouping’s methylene protons experience greater deshielding, due to their proximity to the adjacent imine. Deshielding is an effect of a nearby electronegative atom withdrawing electron density from a given atom nucleus, eliciting an increased chemical shift as measured by NMR.

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