Monensin selective

Metabolism of maduramicin in various animal species seems to proceed in a manner similar to monensin. Selective 0-demethylation of one or two methoxy groups has been reported as the major biotransformation route in chickens and rats (30), whereas O-demethylation of one or more methoxy groups followed by hydroxylation is the major biotransformation route in turkey excreta (31). Conjugation with glucuronic acid also occurs but it is of minor metabolic importance. 

This experiment describes the preparation and evaluation of two liquid-membrane Na+ ion-selective electrodes, using either the sodium salt of monensin or a hemisodium ionophore as ion exchangers incorporated into a PVG matrix. Electrodes prepared using monensin performed poorly, but those prepared using hemisodium showed a linear response over a range of 0.1 M to 3 X 10 M Na+ with slopes close to the theoretical value. 

Individual polyethers exhibit varying specificities for cations. Some polyethers have found appHcation as components in ion-selective electrodes for use in clinical medicine or in laboratory studies involving transport studies or measurement of transmembrane electrical potential (4). The methyl ester of monensin [28636-21 -7] i2ls been incorporated into a membrane sHde assembly used for the assay of semm sodium (see Biosensors) (5). Studies directed toward the design of a lithium selective electrode resulted in the synthesis of a derivative of monensin lactone that is highly specific for lithium (6). 

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... 

Monensin, which is one of the natural antibiotics, selectively transports Na+ across an artificial liquid membrane (organic solvent) from the basic aqueous phase (IN) to the acidic aqueous phase (OUT), driven by the proton gradient8). (Fig. 1, 2)... 

Cholanic acid also possesses the ability of transporting cations across a lipophilic membrane but the selectivity is not observed because it contains no recognition sites for specific cations. In the basic region, monensin forms a lipophilic complex with Na+, which is the counter ion of the carboxylate, by taking a pseudo-cyclic structure based on the effective coordination of the polyether moiety. The lipophilic complex taken up in the liquid membrane is transferred to the active region by diffusion. In the acidic region, the sodium cation is released by the neutralization reaction. The cycle is completed by the reverse transport of the free carboxylic ionophore. 

Z)-2-Butenyldiethylaluminum has been generated at — 78°C by the reaction of (Z)-2-butenylpotassium and diethylaluminum chloride, but its reactions with aldehydes have not been systematically investigated1. The reaction of (Z)-2-butenyldiethylaluminum and chiral aldehyde 1, that provided 2 with 3 1 selectivity, was performed as one step in Still s monensin synthesis. 

Many other cyclic and noncyclic organic carriers with remarkable ion selectivities have been used successfiilly as active hosts of various liquid membrane electrodes. These include the 14-crown-4-ether for lithium (30) 16-crown-5 derivatives for sodium bis-benzo-18-crown-6 ether for cesium the ionophore ETH 1001 [(R,R)-AA -bisd l-ethoxycarbonyl)undecyl-A,yVl-4,5-tctramcthyl-3,6-dioxaoctancdiamide] for calcium the natural macrocyclics nonactin and monensin for ammonia and sodium (31), respectively the ionophore ETH 1117 for magnesium calixarene derivatives for sodium (32) and macrocyclic thioethers for mercury and silver (33). 

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

Macrocyclic compounds with ion-chelating properties occur naturally and often function as ionophores, translocating ions across biological membranes many of these compounds are small cyclic polypeptides. Some natural carboxylic polyethers are selective for Li+ and are, therefore, ionophores for Li+. Monensin, shown in Figure Id, is a natural ionophore for Na+ but it will also complex with Li+ and it has been shown to mediate the transport of Li+ across phospholipid bilayers [21]. It has been proposed that synthetic Li+-specific ionophores have a potential role as adjuvants in lithium therapy, the aim being to reduce the amount of... 

Although the acidic antibiotics do not show the high selectivity characteristic of the neutral ones, there is still some preference, a strong one for monovalent as compared with divalent cations, and within the monovalent cations a variation from one acid to another. Monensin prefers sodium to potassium. The larger nigeridn, (X7), prefers potassium to sodium its silver, potassium, and sodium salts are isomorphous and anhydrous. Crystal structure determinations on the silver salt were carried out independently by workers in the U.S.A. (78) and in Japan... 

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). 

The calculations discussed in the previous two sections show that there is no simple explanation of the ion selectivity of nigericin and monensin in terms of their coordination geometries. A model compound corresponding to nigericin ( = 5, Ar =0A), but fully flexible, would tend to exhibit... 

The discrepancies have to be attributed to differences in AGd, i.e. deformation energy to adjust the size of the preformed cavities to the cationic radii. It seems reasonable to assume a smaller cavity for monensin, because of its shorter skeleton and somewhat higher flexibility (fewer rings) as compared to nigericin. Thus, the differences in selectivity behavior of nigericin and monensin can qualitatively be accounted for. 

Both monensin (24) and nigericin (25) complex Na+ and K+ strongly but not selectively. The crystal structures of the Na+, Tl+ and Ag+ complexes all show the metal ion to be in an O-rich cavity. The carboxylate group is not involved however.97 With the antibiotics (26), (27) and (28) the thermodynamic stabilities (Table 9) are greater for the divalent than for the monovalent metal ions.98 The conformations adopted in these complexes axe very solvent dependent, and the implication of these to the biological transportation of the cations has been discussed.99... 

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. 

Selected examples of other biocatalytic asymmetric oxidations are shown in Figure 20.10. In the area of the polyether ionophore monensin a recently proposed mechanism of oxidative cycUzation of a linear polyketide intermediate by four enzymes, the products of monBI, monBll, monCI, and monCII, has been supported experimentally by analysis of a biosynthetic gene cluster [110] and the accumulation of an B,F,F-triene, when oxidative cydization was blocked [111]. 

Toxins - ionophores There are a number of toxins that form membrane pores that are permeable to physiological inorganic ions, and are very toxic in all cells including neurons (e.g. A23187, a-toxin, melittin, monensin, palytoxin and pardaxin). However, they are not selective for neurons. 

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