Antamanide complexes

Because the stability constant of its complex with potassium is much greater than that with sodium, valinomycin is a relatively specific potassium ionophore. In contrast, the mushroom peptide antamanide has a binding cavity of a different geometry and shows a strong preference for sodium ions.388,390 The structure of the Na+-antamanide complex is also shown in Fig. 8-22B. The Streptomyces polyether antibiotic monensin (Fig. 8-22D),389,391 a popular additive to animal feeds, is also an ionophore. However, its mode of action, which involves disruption of Golgi functions, is uncertain 392... 

Figure 8-22 (A) Uncomplexed valinomycin and its complex with K+ (from Duax et al.387). (B) Stereodiagram of the Na-[Phe4, Val6]antamanide complex. A molecule of C2H5OH, which forms the fifth ligand to the Na+, is omitted for clarity. From Karle et al.388 (C) Monensin and its complex with K+. From Pangbom et al.389...

Antamanide is a cyclic decapeptide antibiotic represented as Cyclo Val -Pro -Pro .Ala -Phe -Phe T>ro -Pro -Phe -Phe ). Antamanide also forms very stable complexes with Li and K in nonpolar solvents such as acetonitrile. Hie crystalline structure of Li -antamanide complex has been investigated 137). It has been made clear that two peptide bonds Pro -Pro and Pro -Pro are cis, there are two intramolecular hydrogen bonds, and four carbonyl groups coordinate to li. This structure is depicted in Pig. 32, where the fifth ligand for Li is solvent acetonitrile. This... 

Fig. 32. Conformation of Li -antamanide complex. ( ), K (crrd), backbone of antamanide ...

Only one C=0 signal was shifted downfield appreciably (2.3 ppm) for the Na+ -antamanide complex. 

I. Karle, K. Karle, Th. Wieland, W. Burgermeister, H. Faulstich, B. Witkop, Conformation of the Li-antamanide complex and Na- (Phe, Val )-antamanide complex in the crystalline state, Proc. Natl. Acad. Sci. USA 70 1836-1840 (1973)... 

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

Complex formation constants measured by several groups using various methods are summarized in Table 2 (for full details see (56)). The antibiotics tabulated prefer K+ relative to Na+, except monensin and antamanide, which prefer Na+ relative to K+. These findings are in agreement with ion-selectivity sequences observed in biological systems (6, 57-61). 

I would like to extend Prof. Simon s characterizations of these beautiful new molecules to include a description of the effects on lipid bilayers of his Na+ selective compound number 11, which my post-doctoral student, Kun-Hung Kuo, and I have found to induce an Na+ selective permeation across lipid bilayer membranes [K.-H. Kuo and G. Eisenman, Naf Selective Permeation of Lipid Bilayers, mediated by a Neutral Ionophore, Abstracts 21st Nat. Biophysical Society meeting (Biophys. J., 17, 212a (1977))]. This is the first example, to my knowledge, of the successful reconstitution of an Na+ selective permeation in an artificial bilayer system. (Presumably the previous failure of such well known lipophilic, Na+ complexing molecules as antamanide, perhydroan-tamanide, or Lehn s cryptates to render bilayers selectively permeable to Na+ is due to kinetic limitations on their rate of complexation and decomplexation). 

The existence of clathrate-like water structure adjacent to the hydrophobic surfaces of macromolecules is an attractive hypothesis. Models have been proposed which have received some support from thermodynamical arguments [808]. However, this concept has proved ineffective as a basis for the interpretation of the structure associated with the many electron density solvent peaks, separated by 2.8 A to 3.0 A, which are frequently observed on the Fourier X-ray maps close to the surface of a protein [809, 810], Recently, however, some local clathrate-like water has been observed in special cases in the high-resolution studies of the small plant protein, crambin [811], in a hydrated deoxydinucleoside-phosphate drug complex [812], in (Phe4Val6) antamanide hydrate [8131 and in an oligodeoxy-nucleotide duplex [814],... 

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. 

Another compound studied was antamanide. It is a cyclic decapeptide isolated from amanita phalloides. Its structure was determined by Th. Wisland and his coworkers 34). This compormd was also found to have carrier properties, however with a pronounced Na+ specificity. The relaxation time of the complex formation process between antamanide and Na+ is in the millisecond range 35). It could therefore be investigated by means of the T-jump technique. 

Table 10. Stability constants of complex formation of antamanide analogs with sodium and potassium in several solvents... 

Table 11. Stability constants of the Na+ complex and antitoxic activity of antamanide and some...

Despite its complex formation ability, antamanide does not mediate ion transport through artificial or biological membranes. This is probably due to its poor... 

Among the alkaline earth metal ions, Ca++ is bound strongly, whereas only weak binding occurs with Sr++ and Ba++, and no interaction with Mg++. CD spectral changes also indicated complex formation with Tl+. Antamanide exhibits clearly a preference for ions of about 1 A radius. 

Elucidation of the complex conformation of antamanide has also been a gradual process. From the first analysis on the basis of IR, ORD, and NMR spectra, a bracelet conformation similar to the valinomycin-K+ complex was proposed, possessing all-... 

Fi. 40. Conformation of the antamanide-Li complex, crystallized from acetonitrile. The phenyl groups of Phe5 and Phe10 have been omitted for clarity. 

Recent CD and NMR studies have demonstrated the ability of antamanide to form also 2 1 peptide-cation complexes with Na+ and Ca++ ions134 A possible sandwich structure of these complexes was proposed by Ivanov and Ovchinnikov, taking into account the described coordination pattern of antamanide (Fig. 42)218 ... 

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