Valinomycin

Valinomycin is a macrocyclic dodecadepsipeptide with 12 subunits — amino- and hydroxycarboxylic acids — which are connected by alternate peptide and ester bonds. It consists of three identical fragments D-Hylv-D-Val-L-Lac-L-Val (Fig. 1). Although the valinomycin structure has been discussed in a recent review on complex formation of monovalent cations with biofunctional ligands it is described here in some detail 

Only rubidium whose ionic radius is close to that of potassium is bound at least as effectively as the latter. An X-ray structural analysis of the valinomycin-RbAuQ complex revealed essentially the same structure as in the complex, the octahedral cage of the oxygen atoms being by only 0.04 A wider due to minor rotations of the ester bonds 

Numerous spectroscopic studies and a conformational energy calculation of the solution conformation of the valinomycin-K complex are in good agreement 

These 5- l bonds are largely responsible for the oval shape of uncomplexed valinomycin. Moreover, they direct two of the ester carbonyl oxygens toward the surface of the molecule (see Fig. 4). These might serve as initiators of complex formation by interaction with the metal ion prior to the placement of the latter in the ligand cavity. Based on this assumption. Smith and Duax developed a simplified model for the complexation process They proposed that the formation of the initial loose complex with the potassium ion is followed by cleavage of both the 5- l type hydrogen bonds in order to enable all the other ester carbonyl oxygens to interact with the cation and to replace the molecules of its solvation shell one after another. 

The three X-ray diffraction studies of uncomplexed valinomycin actually revealed structures of five independent molecules. They all exhibit lar ly the same conformation, although the crystals were grown from solvents of different polarity and showed different modes of molecular packing and solvent contents. This finding strongly suggests that crystal packing forces do not markedly affect the conformation of valinomycin molecules in the solid state and justifies the assumption that this 

In 1955, H. Brockmann and Schmidt-Kastner [15] isolated an antibiotic substance from extracts of Streptomyces fulvissimus. They named it valinomycin after valine having been found as the only amino acid in the acid-hydrolyzate. Since no amino group nor carboxyl group could be detected in the substance which was almost insoluble in water, a cyclic structure had to be assumed. Valinomycin has a macrocyclic molecular structure consisting of three identical tetradepsipeptide fragments with alternating peptide and ester bonds between D-a-hydroxyisovaleric acid, D-valine, L-lactic add, L-valyl residues (Fig. 10). 

The antibiotic has been found to be active against a number of bacteria, yeasts, and fungi, and later to uncouple oxidative phosphorylation of mitochondria. 

In 1964, Moore and Pressman [16] discovered that vaiinomydn induces K -uptake in mitochondria. By various methods it was then demonstrated that in alcoholic solution the depsipeptide forms very stable complexes with K, Rb and Cs -ions. Since then the investigation of mechanisms by which certain substances facilitate ion transport in lipid membranes has developed into a major field in biophysics. Besides the carrier transport mentioned here, there also exists a channel mechanism. 

The stability constant, Kgtab, of the potassium-valinomycin complex in ethanol is rather high (ca. 10 /M vs 10 VM with Na ), hence the conformation of the K complex in solution is rigid, therefore stable and well defined. The geometry of the complex has been determined by the combined use of spectroscopic methods in several laboratories of which here only the results of 

In both structures, which agree rather well, the K -ion is totally encapsulated, coordinated with six carbonyl oxygen atoms of ester groups in a nearly regular octahedron. 

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This experiment describes the preparation of a flow-through potentiometric electrode assembly incorporating a valinomycin-PVC membrane in the transport tubing. The... 

Valinomycin and the Enniatins. Neutral ionophores such as the cycHc dodecadepsipeptide valinomycin [2001-95-8] C H QN O g, (Fig. 8) from StreptomjcesJulvissimus (179), and the cycHc hexadepsipeptides enniatin [11113-62-5] and beauvericin [26048-05-5] from fungi (180—182),... 

Fig. 8. Stmcture of (a) valinomycin and (J3) and enniatins and beauvericin. Hov = a-hydroxy-isovaleric acid and Lac = lactic acid. The /V-methylamino acid for enniatin A is isoleucine enniatin B, valine enniatin C, leucine and beauvericin, phenylalanine.

The enniatins enniatin A [2503-13-17, C gH N Og, enniatin B [917-13-5] C23H yN202, enniatin C [19893-23-3], C Hg N Og, and beauvericin (Fig. 8) are 700—800 molecular weight cycHc hexadepsipeptides. They form valinomycinlike hydrophilic cavities surrounded by outer lipophilic regions, but they have more flexible stmctures than those seen with valinomycin and therefore have less specificity for potassium over sodium ion than valinomycin (186,187). 

MacrotetroHdes of the valinomycin group of electrically neutral antibiotics form stable 1 1 complexes with alkaH metal ions that increase the cation permeabiHty of some biological and artificial lipophilic membranes. This solubiHzation process appears to have implications in membrane transport research (30) (see Antibiotics, peptides). 

Of interest is the manner in which cavities of the appropriate size are introduced into ion-selective membranes. These membranes typically consist of highly plasticized poly(vinyl chloride) (see Membrane technology). Plasticizers (qv) are organic solvents such as phthalates, sebacates, trimelLitates, and organic phosphates of various kinds, and cavities may simply be the excluded volumes maintained by these solvent molecules themselves. More often, however, neutral carrier molecules (20) are added to the membrane. These molecules are shaped like donuts and have holes that have the same sizes as the ions of interest, eg, valinomycin [2001-95-8] C H QN O g, and nonactin [6833-84-7] have wrap around stmctures like methyl monensin... 

Valence shell electron pair repulsion theory, 1, 564 Valence tautomerism photochromic processes and, 1, 387 y-Valerolactone, o -allyl-a -2-(pyrido[2,3-6]-imidazolyl)-synthesis, 5, 637 Validamycin A as fungicide, 1, 194 Valinomycin... 

The X-ray crystal structures of many of these complexes have now been determined representative examples are. shown in Fig. 4.11 from which it is clear that, at least for the larger cations, coordinative saturation and bond rhrectionality are far less significant factors than in many transition element complexes. Further interest in these ligands stems from their use in biochemical modelling since they sometimes mimic the behaviour of naturally occurring, neutral, macrocydic antibiotics such as valinomycin, monactin, nonactin, nigericin... 

This review addresses the issues of the chemical and physical processes whereby inorganic anions and cations are selectively retained by or passed through cell membranes. The channel and carrier mechanisms of membranes permeation are treated by means of model systems. The models are the planar lipid bilayer for the cell membrane, Gramicidin for the channel mechanism, and Valinomycin for the carrier mechanism. 

With respect to the carrier mechanism, the phenomenology of the carrier transport of ions is discussed in terms of the criteria and kinetic scheme for the carrier mechanism the molecular structure of the Valinomycin-potassium ion complex is considered in terms of the polar core wherein the ion resides and comparison is made to the Enniatin B complexation of ions it is seen again that anion vs cation selectivity is the result of chemical structure and conformation lipid proximity and polar component of the polar core are discussed relative to monovalent vs multivalent cation selectivity and the dramatic monovalent cation selectivity of Valinomycin is demonstrated to be the result of the conformational energetics of forming polar cores of sizes suitable for different sized monovalent cations. 

In what follows, the phenomenology of carrier transport will be briefly reviewed along with the mechanism of the Valinomycin model of carrier transport. The development of the molecular structure of Valinomycin will be considered in some detail, since the key to the dramatic selectivity of Valinomycin is thought to reside in the energetics of the molecular structure. Confidence in an understanding of the molecular structure of the Valinomycin-cation complex becomes tantamount to confidence in the presented basis of ion selectivity. 

Fig. 17. Membrane current, Xq, of a dioleoyllecithin membrane, A. as a function of Valinomycin concentration at 1 M KC1 and B. as a function of KC1 concentration at 10"7 M Valinomycin. The linearity and slope of one indicates a carrier mechanism with a 1 1 carrier to cation stoichiometry. Reproduced with permission from Ref.811...

The kinetic scheme applicable to the Valinomycin carrier system is given in Fig. 18 where S is the carrier and MS+ is the carrier-cation complex. There are five unknown parameters, the four rate constants and Ns, the interfacial concentration of... 

Fig. 18. Kinetic scheme for the Valinomycin carrier mechanism of transport. Reproduced with permission from Ref. 87)...

Fig. 19. Space filling models of the molecular structure of the Valinomycin-potassium ion complex as originally determined.

Fig. 20. A. Conformation of the Valinomycin-cation complex derived for solution using a combination of proton magnetic resonance data and conformational energy calculations. This structure agrees within tenths of an Angstrom with the crystal structure subsequently determined (100) and shown in Fig. 21. Reproduced with permission from Ref.99).

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