Enniatins metal complexes

The symmetrical ring enniatin (304) forms a potassium complex (Figure 9.3) whose crystal structure indicates that the cation is contained in the macrocyclic cavity and is coordinated by the six carbonyl oxygen atoms which are orientated such that three lie above and three lie below the main plane of the molecule (Dobler, Dunitz Krajewski, 1969). Apart from those just discussed, it needs to be noted that a range of other structures of antibiotic molecules and their metal complexes have been determined (Hilgenfeld Saenger, 1982). 

Great attention has been paid to the excellent metal-complexation properties of cyclic peptides. 1 615 631 Naturally occurring examples include enniatin, valinomycin, 616 or antama-nide, 316 and cyclosporin A. 632 Several libraries of cyclic peptides have been synthesized to address these properties, 402 but also bicyclic peptides have been synthesized in this context. t617-620 ... 

The compounds form 1 1 complexes with all alkali ions and with a large number of other metal ions in organic solvents267,268,307. Among the alkali ions, K+ is bound most strongly, but K+-complex stability as well as K+ > Na+ selectivity are much less pronounced than with valinomycin. In concentrated enniatin solutions, non-equimolar complexes are formed. NMR- und CD-spectroscopic titrations have demonstrated that 2 1 enniatin-cation complexes are formed with a stability order of K+ > Cs+ > Na+. Evidence for formation of a 3 2 complex with Cs+ was also obtained133,216 ... 

The hexapeptide, cycb( L-Pro-Gly)3, has been shown to form complexes with a number of metal ions175 The compound exhibits ion selectivity for Li+ and Na+ over K+ and larger alkali metal ions. It also forms a Ca++ complex which has a stability constant in acetonitrile of stab = 1.1 x 10s M 1. With Mg++ three different complexes with cyclopeptide-cation stoichiometries of 2 1,1 1, and 1 2 are formed. Hypothetical structures of these complexes (Fig. 45) have been proposed which are reminiscent of the enniatin sandwich complexes. 

The structure of the enniatin B complex with potassium iodide has been studied by X-ray crystallography Unfortunately, from this investigation it could not be concluded with certainty whether the metal ion is entrapped in the central cavity or, instead, occupies a site between two adjacent ligand molecules. An arrangement of the latter type has been observed in the crystal structure of the 1 1 complex between RbNCS and the synthetic LDLLDL isomer of enniatin B In this case, Rb" ions are coordinated by five carbonyl oxygens (three of the upper and two of the lower depsipeptide molecules) and the nitrogen atom of the isocyanate anion, thus forming infinite sandwiches. 

The mechanistic problems associated with the transport of cations (especially Na and K+) through membranes have continued to receive attention. The structures of macrocyclic alkali-metal complexes and the thermodynamics of their formation have been reviewed, as has the general question of the selectivity of the carriers towards the metals. The role of hydration energy has been considered and it has been suggested that, at least in the case of the enniatin ionophores, sandwich... 

The alkali metal cation complexes of compounds of the valino-mycin group (valinomycin, enniatins, macrotetrolides, beauveridn, antamanide) are positively charged. 

The enniatins and beauveracin are cyclic hexadepsipeptides and so are 18-membered macrocycles built up of alternating amino acid and carboxylic acid residues. They exhibit lower selectivity than (137) and consequently are more broad spectrum ionophores. The structure of (138)KI has been solved544 but it was not possible to conclude, with certainty, whether the metal is entrapped in the central cavity, as in related cyclic polyether structures (Figure 14a), or whether it occupi.es a site between two adjacent ligand molecules to give an infinite sandwich (147) as has been found in the RbNCS complex of a synthetic ldlldl isomer of (138).545 Adducts of 1 2 sandwich and 2 3 club sandwich stoichiometry have been proposed for Cs+ complexes of (138),546a and the 1 2 K+ sandwich complex of (138) has been proposed as the species which transports K+ across lipid layers as it shields the metal effectively from solvent interactions.5461 ... 

The association constant for ion binding of Cyclo-(Pro-Gly)3 b nearly the same as that of antamanide, but the selectivity for Ca of Cydo-(Pro-Gly)3 is inferior to that for Na" " of antamanide (144). Cyclo-(Pro-Gly)3 resembles the K -specific cyclic hexadepdpeptide aiitibiotic enniatin (145), in the aspect that both cycUc compounds form sandwich-type comjdexes with ions. It is very likely that Cyclo-(Pro y)3 transports ions across a membrane vb the formation of a club sandwich-type complex. The metal-ion complex of Cyclo-(Pro<]tly)3 is extractable with water from organic phase. A specific behavior of clo-(Pro-Gly)3 in the ion tran rt throu a membrane b expected from fhb property. 

The conformational studies on the ferrichromes and on ferrioxamine B indicate that a number of intramolecular hydrogen bonds are formed in the process of metal-chelation and that these contribute to the overall stability of the coordinated conformation relative to that of the free species. Consistent with this view, it should be mentioned that extensive hydrogen bonding has also been observed in the low molecular weight monovalent cation complexes of the antibiotics monensin, nigericin, dianemycin, the enniatins and valinomycin by NMR spectroscopy (69, 70), X-ray crystallography (71, 72, 73), or both. Like the siderochromes, these compounds act by mediating cation fluxes across membranes. 

In the cases of valinomycin and enniatin depsipeptides described in Section 2. the explanation for the structural origins of the more or less pronounced ion selectivities exhibited by these antibiotics was, though being plausible, somewhat tentative, as completed X-ray analyses were available only for complexes with a single ion species, i.e. with for valinomycin and Ba " for beauvericin. However, a detailed discussion of the structural features that lead to metal ion selectivities should be based on a whole set of comparable data on complex structures with various metal ions of... 

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