Valinomycin selective binding

Although rum ammonia levels are not routinely measured, it is a useful indicator of Reye s syndrome and should be monitored in newborns at risk of developing hyperammonemia Ammonia is produced in many analytically useful enzyme reactions and the ammonium ISE has been used as the base sensor in several enzyme electrodes (see next section). In addition to valinomycin, other antibiotics such as the nonactin homalogs and gramicidins also behave as ionophores. The nonactin homolo were originally studied for their ability to selectively bind potassiiun ions It was then discovered that ammonium ions were preferred over potassium ions, and the selectivity coefficient Knh+ = 0.12 was reported. Since ammonia is present at fairly low levels in serum, this selectivity is not sufficient to to accurately measure NH4 in the presence of K. An extra measure of selectivity can be gained by using a gas permeable membrane to separate the ammonia gas from the sample matrix... 

Materials with selective binding or transport properties will have a major impact on sensor design and fabrication. Selectivity in either binding or transport can be exploited for a variety of measurement needs. This selectivity can be either intrinsic, that is, built into the chemical properties of the material, or coupled with selective carriers that allow a non-selective material to be converted into a selective one (see the section on recognition chemistry). An example of the latter is the use of valinomycin as a selective carrier in a polyvinyl chloride membrane to form a potentiometric potassium ion sensor. Advances in the fields of gas separation materials for air purification and membrane development for desalinization are contemporary examples illustrating the importance of selective materials. As these materials are identified, they can be exploited for the design of selective measurement schemes. 

For examfde, cydic dodecadepsipeptide antibiotic valinomycin (18) is refure-sented as Cydo-(D-Val-Lac-Val-D-Ifyv)3 where Lac and Hyv re esent lactic add and cr-oxyisobutyric add, re ctively. ValinonQrcin selectively binds K, when it acts as an antibiotic. As shown in Fig. 31, valinomycin takes a bracelet structure and has a cavity in the middle with a diameter of 6—7A. Sizes of hydrated cations are... 

Naturally occurring valinomycin [129], nonactin [130], antamanide [131], beauvericin [ 13 21 and entcrobactin [133] are analogous to synthetic crow n ethers in that they possess polar cavities which can strongly and selectively bind cations and act as ion carriers in model and biological membranes (Fendler and Fendler,... 

For examfde, cyclic dodecadepsipeptide antibiotic valinomycin (18) is represented as Cyclo D-Val-Lac-Val-D-ifyv)3 where Lac and Hyv re esent lactic acid and a-oxyisobutyric add, re ctively. ValinoiiQrcin selectively binds K, when it acts as an antibiotic. As shown in Fig. 31, valinomycin takes a bracelet structure and has a cavity in the middle with a diameter of 6—7A. Sizes of hydrated cations are 4.5—5.0 A for K, Rb, and Cs and 5.5—7.4 A for Na and Li . It is understandable that the cavity fits in with K. Carbonyl groups are distributed along the inside wall of the cavity which is necessarily polar. Alifdiatic side chains form the outside wall of the bracelet whidi is necessarily nonpolar. Valinomycin binds in the hydro-0ulic interior of the cavity and transports the ion across the lipid bilayer of the cell... 

Electronic signals in nerve cells travel by means of metal-ion transport laterally in and out of the axon. Such transmembrane transport of ions is fundamental to cell biology, and attempts to mimic it artificially laid the foundation of supramolecular chemistry. Early studies in molecular recognition by Lehn in the 1970s explored the use of crown ethers as mimics of cyclic peptide ionophores like valinomycin, which bind cations selectively in their internal cavities. Natural ionophores act as antibiotics by upsetting the ionic balance across bacterial cell walls. 

Figure 15-6b shows how the electrode works. The key in this example is the ligand, L (called an ionopkore), which is soluble inside the membrane and selectively binds analyte ion. In a potassium ion-selective electrode, for example, L could be valinomycin, a natural antibiotic secreted by certain microorganisms to carry ion across cell membranes. The ligand L is chosen to have a high affinity for analyte cation and low affinity for other ions. 

ISEs for li+, K+, Ca " ", and Mg + have been developed on the basis of liquid membranes that contain ionophores these are hydrophobic chelating agents that contain selective binding sites for the ion of interest. While the structures of ionophores used in commercially available devices are often proprietary, examples of well-studied ISE ionophores include 14-crown-4 ether for li+ [20] and valinomycin for K" " [21]. Valinomycin is 5000 times more selective toward K+ over Na" " and 18000 times more selective toward K+ over H+. 

Natural receptors, such as valinomycin or beauverin, can be used as carriers. Also synthetic receptors have been developed. The first generation of synthetic carriers were the crown ether macrocycles, which selectively bind alkali metal ions 4). Since their discovery in 1967, many other types of macrocycles have been synthesized and used for the selective recognition of neutral, charged, or zwitter-ionic species. Many have been used as carriers in liquid membranes (5). 

Liquid ion-exchange electrodes where the membrane consists of a solvent in which is dissolved an ion-selective carrier, e.g. valinomycin which binds or dioctyl phosphate which binds calcium. This latter membrane is used for the measurement of ionized calcium in serum. 

Fig. 16. The antibiotic ligands (a) monensin, which binds Na+ selectively, and (b) valinomycin and (c) enniatin-B, which bind K+ selectively.

Especially sensitive and selective potassium and some other ion-selective electrodes employ special complexing agents in their membranes, termed ionophores (discussed in detail on page 445). These substances, which often have cyclic structures, bind alkali metal ions and some other cations in complexes with widely varying stability constants. The membrane of an ion-selective electrode contains the salt of the determined cation with a hydrophobic anion (usually tetraphenylborate) and excess ionophore, so that the cation is mostly bound in the complex in the membrane. It can readily be demonstrated that the membrane potential obeys Eq. (6.3.3). In the presence of interferents, the selectivity coefficient is given approximately by the ratio of the stability constants of the complexes of the two ions with the ionophore. For the determination of potassium ions in the presence of interfering sodium ions, where the ionophore is the cyclic depsipeptide, valinomycin, the selectivity coefficient is Na+ 10"4, so that this electrode can be used to determine potassium ions in the presence of a 104-fold excess of sodium ions. 

Although some scattered examples of binding of alkali cations (AC) were known (see [2.13,2.14]) and earlier observations had suggested that polyethers interact with them [2.15], the coordination chemistry of alkali cations developed only in the last 30 years with the discovery of several types of more or less powerful and selective cyclic or acyclic ligands. Three main classes may be distinguished 1) natural macrocycles displaying antibiotic properties such as valinomycin or the enniatins [1.21-1.23] 2) synthetic macrocyclic polyethers, the crown ethers, and their numerous derivatives [1.24,1.25, 2.16, A.l, A.13, A.21], followed by the spherands [2.9, 2.10] 3) synthetic macropolycyclic ligands, the cryptands [1.26, 1.27, 2.17, A.l, A.13], followed by other types such as the cryptospherands [2.9, 2.10]. 

The question of carrier design was first addressed for the transport of inorganic cations. In fact, selective alkali cation transport was one of the initial objectives of our work on cryptates [1.26a, 6.4]. Natural acyclic and macrocyclic ligands (such as monensin, valinomycin, enniatin, nonactin, etc.) were found early on to act as selective ion carriers, ionophores and have been extensively studied, in particular in view of their antibiotic properties [1.21, 6.5]. The discovery of the cation binding properties of crown ethers and of cryptates led to active investigations of the ionophoretic properties of these synthetic compounds [2.3c, 6.1,6.2,6.4-6.13], The first step resides in the ability of these substances to lipophilize cations by complexation and to extract them into an organic or membrane phase [6.14, 6.15]. 

The antibiotics are compounds secreted by microbes that enhance the permeability of membranes to cations. One class functions by binding a metal to give a liposoluble complex that can then pass across the membrane. Examples are valinomycin, a cyclic peptide that binds K+ selectively, and monensin which binds Na+. These too are oxygen-donor ligands, and will be discussed in the following section. They function as antibiotics because they allow the concentrations of a cation across membranes to become equalized, and so cause the collapse of the membrane potential. 

Fig. 6.15 (a, b) Neutral ionophore valinomycin with the cavity for binding potassium ion. (c) Charged ionophore di n-octyl phenyl phosphonate used in calcium ion-selective electrodes... 

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