Structure of cereulide, a cyclic dodecadepsipeptide toxin from Bacillus cereus and studies on NMR characteristics of its alkali metal complexes including a conformational structure of the K+ complex

Abstract

The structure and stereochemistry of cereulide 1 or 1a, an emetic toxin produced by Bacillus cereus, have been determined through spectral analysis and chemical methods. It is a 36-membered cyclic depsipeptide with the sequence of cyclo(D-O-Leu-D-Ala-L-O-Val-L-Val)₃. The outstanding property of cereulide is a Rb⁺-and K⁺-ion-selective ionophore, the same as in valinomycin 2. Cereulide forms a 1:1 complex with alkali metal ions. Owing to its structural similarity to valinomycin 2 and our well established conformational knowledge about compound 2, the NMR data of cereulide–alkali metal complexes in chloroform gave us a partial view of the conformational structure in solution and a calculated modelling of the complex with K⁺ is proposed. The main chain shows a hexagonal cyclinder-like framework which is similar to the known bracelet-like structure of the valinomycin–K⁺ complex. All amide carbonyls arrange along the cylindrical side-wall planes so that they can form β-turn hydrogen bonds with NH protons. Every alpha carbon is located at a corner in both the top and the bottom planes, enabling alpha protons of oxy acids to turn inwards towards the cavity and those of the amino acids turn outwards. The K⁺ is centrally situated in the cavity of the host cereulide by the ion–dipole interactions with three carbonyl oxygens of L-Val in the top plane and the three carbonyls of D-Ala in the bottom plane. The experimental coupling constant and NOE data of the K⁺ complex had conformity with the calculated dihedral angle and distance measured from the proposed conformational structure. Partial views of the conformations of cereulide complexed with Li⁺ and Na⁺ are analysed as follows: The frameworks of the Li⁺ complex main chain lose their compactness, becoming more linearly extended, which results in a bigger cavity diameter, have fewer hydrogen bonds, and all the residual side-chains can freely rotate whereas the conformation(s) of the Na⁺ complex takes the intermediate conformation(s) between those of the highly stable (the K⁺ and Rb⁺) and that of the less stable (the Li⁺) complexes.