Lipid soluble cation complexes

There appear to be two major ways by which ionophores aid ions to cross membrane barriers. Ionophores such as valinomycin and nonactin enclose the cation such that the outside of the complex is quite hydro-phobic (and thus lipid-soluble). The transport behaviour thus involves binding of the cation at the membrane surface by the antibiotic, followed by diffusion of the complexed cation across the membrane to the opposite surface where it is released. Such carrier type ionophores can be very efficient, with one molecule facilitating the passage of thousands of ions per second. A prerequisite for efficient transport by this type of ionophore is that both the kinetics of complex formation and dissociation be fast. 

A great number of ligands, such as the anions of ethylenediamine-NNN N -tetra-acetic acid (EDTA), described in detail by Schwarzen-bach and his school (29, 30), show a pronounced selectivity for alkaline earth and other metal cations (30). Because of the limited lipid solubility of these ligands and their complexes, such compounds are, however, not suited as ion carriers in lipophilic membranes (Fig. 2). The ability... 

Since the discovery in 1964 that the antibiotic valinomydn exhibited alkali cation specificity in rat liver mitochondria, a new area of research has developed, based not only on biological systems but also on model systems such as crown ethers.484 The ability of neutral compounds to form lipid-soluble alkali and alkaline earth complexes was observed in 1951. The structure of the corresponding ligand, the anion of the antibiotic nigericin (78), was characterized as its silver salt in 1968.488 486 Silver was used as a heavy atom crystaUographically, since the Ag+ cation had a radius between that of Na+ and K+, which were the two alkali cations with which nigericin was most active. 

A further group of biologically available chemical species comprises organic compounds of the trace elements, which may be divided into two groups organic complexes of cations, and metal and non-metal alkyls (Table 3). These species are mainly neutral molecules, in contrast to the ionic species identified in Table 2, and are thought to be taken up as a consequence of their lipid-solubility (Florence et al., 1983). 

A group of antibiotics (e.g., valinomycin, nigericin, and gramicidin A) transport cations across the cell membrane. Such agents, known as ionophores, are widely used to probe membrane structure and function. Ionophores uncouple oxidative phosphorylation. Valinomycin, a cyclic peptide (Figure 14-17), forms a lipid-soluble complex with K+ that readily passes through the inner membrane, whereas K+ by itself does not. In the valinomycin-K complex, hydrophobic groups, present on the outside, facilitate transport of the complex in the lipid environment ... 

Neutral lonophores. The relationship between equilibrium ionophore affinities and dynamic biological transmembrane transport is detailed in Figure 2. The transport cycle catalyzed by neutral ionophores is given on the left. Ionophore added to a biological membrane partitions predominately into the membrane. A portion of the ionophore diffuses to the membrane Interface where it encounters a hydrated cation. A loose encounter complex is formed followed by replacement of the cationic hydration sphere by engulfment of the cation by the ionophore. The dehydrated complex is lipid-soluble and hence can diffuse across the membrane. The cation is then rehydrated, released, and the uncomplexed lono-phore freed to return to its initial state within the membrane. 

Pharmacokinetics of lonophore Absorption. We have developed a sensitive chemical assay for carboxylic lonophores (which will be published elsewhere) based on their ability to form lipid soluble complexes with cations. We can detect as little as 1 part per billion (ppb) monensin in 2 ml of blood plasma or tissue. For a comparison yardstick, current feeding regimens call for ca. 30 parts per million (ppm) in cattle feed (32) and as much as 100 ppm in poultry feed (33). 

The molecular basis of action of the ionophore antibiotics involves their ability to form lipid-soluble complexes with metal ions. Mueller and Rudin [182] suggested that the macrocyclic ionophores form coordination complexes by hydrogen bonding and dipole interactions between the cation and the carboxyl oxygen atoms of the antibiotics which project towards the centre of the ring. The carboxyl oxygen atoms of the antibiotic replace the water molecules in the hydration shell of the cation. Complexes of this type involving K ions... 

The antimicrobial activity described here is only valid for 8-hydroxyquinoline and not for the seven other possible hydroxyquinolines which are widely inactive and do not, as does 8-hydroxyquinoline, chelate metal cations, e.g. copper, iron and zinc. Contrary to Oxine the corresponding chelation complexes, e.g. copper 8-hydroxyquinoline (Section 11.5) possess considerable lipid solubility enabling the complex to pass through the cell membrane and then to dissociate into the toxic 8-hydroxyquinoline. However, according to the findings of Block (1983)... 

Lipophilicity. The gross lipophilicity of the ligand and of its complexes plays a very important role whenever substances soluble in organic media of low polarity are needed. This is the case in studies of anion activation and of cation transport through lipid membranes, where salts have to be dissolved in organic phases. The lipophilic character may be controlled via the nature of the hydrocarbon residues forming the ligand framework or attached to it. 

Competition between mono- and di-valent cations has an important role in biological processes. Furthermore, the lipophilicity of a ligand and its complex plays an important role in deciding whether a species is soluble in organic media of low polarity. This has important consequences in areas such as phase-transfer catalysis, the use of crown ethers as anion activators, and in cation transport through lipid membranes. Many crown ethers have now been synthesized with incorporation of long alkyl side chains and enhanced lipophilicity and used successfully in the above areas. 

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