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The alkali-ion binding properties of two natural depsipeptide ion carriers, enniatin B (EnB) and valinomycin (VM), are examined and compared by the empirical force field method. While VM has been shown to bind preferentially K+, Rb+, and Cs+ over Na+ in most solvents, EnB is considerably less specific. We find that EnB forms two kinds of complexes, internal and external. In internal complexes, the ion binds to all six carbonyl oxygens, while in external ones, only three oxygens, preferentially those of the D-hydroxy-isovaleryl residues, are bound. The size of the internal cavity is best suited for Na+, while K+ and Rb+ squeeze in asymmetrically by distorting the molecule, and Cs+ not at all. External binding is much less specific. Since internal complexes possess much higher strain energies than external ones, the latter may be at least as stable as the former, even in fairly non-polar solvents. VM is calculated to bind only internally, and with much less strain energy than EnB. The size of its internal cavity is well suited for binding the ions K+, Rb+, and Cs+, but is too big for Na+. The difference between the binding energies of Na+ and K+ is much smaller than that between the corresponding hydration enthalpies, thus explaining the binding preference for the latter ion.

Molecular orbital calculations using the PCILO method are performed on the conformation of the symmetrical form of enniatin B. The values of the Φ and ψ angles found for the preferred conformation agree closely with the results of X-ray study of the K + complex of enniatin B.

Detailed CD- and UV-studies indicate a conformational change in antamanide by interaction with cations or polar solvents. The conformation formed on addition of water is similar to that of the complex. A model for antamanide already suggested by Ovchinnikov's (1) group is confirmed by CD-data and by substitutions in position 1 and 4 (2). The unusually high negative dichroism at about 230 nm is ascribed to n → π ∗ transitions of transoid tertiary amide groups distorted out of plane. Non planar amides probably also determine the dichroic properties of enniatin B (3) and of some acetylproline derivatives (4).

THE interaction of a biologically active substance with a selective receptor (for instance, substrate and enzyme) to cause a certain physiological effect is chemically complex, requiring not only a certain minimum of steric congruity of the molecules but also a given electron density distribution in the interacting functional centres. If either of these requirements is not satisfied, the reaction will either not take place at all or its effectiveness will be diminished by several orders of magnitude. It is thus important to discover the limits of steric and electronic matching, both in the rational search for substances with similar, modified or antagonistic action, and to understand the underlying mechanism.

Publisher Summary This chapter discusses the structure of and microbiological activity in the Enniatin-series. The cyclic depsipeptide is built up by regularly alternating D-α-hydroxyisovaleric acid and a N-methyl-amino-acid, which in Enniatin A is N-methyl- L-isoleucine and in Enniatin B N-methyl- L-valine. The tertiary butyl ester of D-α-hydroxy-isovaleric acid is coupled by means of benzene sulfochloride to the corresponding benzyloxycarbonyl-amino-acid in the presence of pyridine. By enlarging the decarbobenzoxylated tetradepsipeptide ester used in the Enniatin B synthesis with the didepsipeptide acid containing L-valine, the hexadepsipeptide for the monodesmethyl-product can be obtained. The synthetic route to the tridesmethyl-enniatin B resembles the one used for the synthesis of the Enniatin B, differing only by the use of L-valine instead of N-methyl- L-valine.

The present state of the chemistry of the valinomycin type and enniatin B type depsipeptide ionophores is reviewed. An analysis is carried out on the relation between the primary structure, the conformation, the complexing properties, and the membrane activity of valinomycin and its numerous analogs. The correlations resulting from such a study have made it possible to carry out the predetermined synthesis of valinomycin analogs excelling the parent compound in complexing properties.

Judging by the physical and chemical properties and “bacterial spectra”, the antibiotic substance, Enniatin, previously isolated from a strain ofFusarium by the authors, appears to be identical with that which was recently reported byCook et al. derived from another strain and designated by them as Lateritiin-I, although the reported empirical formulae differ. Numerous physical and chemical characteristics of Enniatin and its degradation products are given, and, further, two relatedFusarium antibiotics, here designated as Enniatin B and C, are briefly described.

Die Struktur von Enniatin B, eines antimikrobiellen Wirkstoffes aus Fusarienstammen (ETH, Zurich), wird durch Synthese als die eines Cyclohexapeptolids bewiesen (vgl. X).

The cyclodepsipeptide beauvericin and a mixture of the cyclodepsipeptides, enniatin A1, enniatin B1, enniatin B and enniatin A, have been isolated from plant pathogenic fungi. Previously, beauvericin has only been isolated from the unrelated entomopathogenic fungi.