Carriers lipid membranes

All of the transport systems examined thus far are relatively large proteins. Several small molecule toxins produced by microorganisms facilitate ion transport across membranes. Due to their relative simplicity, these molecules, the lonophore antibiotics, represent paradigms of the mobile carrier and pore or charmel models for membrane transport. Mobile carriers are molecules that form complexes with particular ions and diffuse freely across a lipid membrane (Figure 10.38). Pores or channels, on the other hand, adopt a fixed orientation in a membrane, creating a hole that permits the transmembrane movement of ions. These pores or channels may be formed from monomeric or (more often) multimeric structures in the membrane. 

Mechanisms of biological ion transport-carriers, channels and pumps in artificial lipid membranes. P. Lauger, Angew. Chem.,Int. Ed. Engl., 1985, 24, 905 (265). 

Adamantane derivatives can be employed as carriers for drug delivery and targeting systems. Due to their high lipophUicity, attachment of such groups to drugs with low hydrophobicity could lead to a substantial increase of drug solubihty in lipidic membranes and thus increases of its uptake. 

A number of substances have been discovered in the last thirty years with a macrocyclic structure (i.e. with ten or more ring members), polar ring interior and non-polar exterior. These substances form complexes with univalent (sometimes divalent) cations, especially with alkali metal ions, with a stability that is very dependent on the individual ionic sort. They mediate transport of ions through the lipid membranes of cells and cell organelles, whence the origin of the term ion-carrier (ionophore). They ion-specifically uncouple oxidative phosphorylation in mitochondria, which led to their discovery in the 1950s. This property is also connected with their antibiotic action. Furthermore, they produce a membrane potential on both thin lipid and thick membranes. 

Other systems like electroporation have no lipids that might help in membrane sealing or fusion for direct transfer of the nucleic acid across membranes they have to generate transient pores, a process where efficiency is usually directly correlated with membrane destruction and cytotoxicity. Alternatively, like for the majority of polymer-based polyplexes, cellular uptake proceeds by clathrin- or caveolin-dependent and related endocytic pathways [152-156]. The polyplexes end up inside endosomes, and the membrane disruption happens in intracellular vesicles. It is noteworthy that several observed uptake processes may not be functional in delivery of bioactive material. Subsequent intracellular obstacles may render a specific pathway into a dead end [151, 154, 156]. With time, endosomal vesicles become slightly acidic (pH 5-6) and finally fuse with and mature into lysosomes. Therefore, polyplexes have to escape into the cytosol to avoid the nucleic acid-degrading lysosomal environment, and to deliver the therapeutic nucleic acid to the active site. Either the carrier polymer or a conjugated endosomolytic domain has to mediate this process [157], which involves local lipid membrane perturbation. Such a lipid membrane interaction could be a toxic event if occurring at the cell surface or mitochondrial membrane. Thus, polymers that show an endosome-specific membrane activity are favorable. 

Liposomes are membrane-based supramolecular particles that consist of a number of concentric lipid membrane bilayers separated by aqueous compartments (Figure 13.15). They were developed initially as carriers for therapeutic drugs. Initially, the bilayers were almost exclusively phospholipid based. More recently, non-phospholipid-based liposomes have been developed. 

A different direction in ion-selective electrode research is based on experiments with antibiotics that uncouple oxidative phosphorylation in mitochondria [59]. These substances act as ion carriers (ionophores) and produce ion-specific potentials at bilayer lipid membranes [72]. This function led Stefanac and Simon to obtain a new type of ion-selective electrode for alkali metal ions [92] and is also important in supporting the chemi-osmotic theory of oxidative phosphorylation [69]. The range of ionophores, in view of their selectivity for other ions, was broadened by new synthetic substances [1,61]. 

Some authors have used carrier-free enzymatic incubation mixtures at pH 8.0-8.3 (J5, P3, W12). In general, the final concentrations used (incubation at 37°C) were 5-10-fold higher than the solubility of bilirubin at 25°C (B25). Although solubility data at 37°C are not available, it is likely that in most instances the solubility was exceeded. It is not known whether, and to what extent, bilirubin is solubilized in an aspecific way, e.g., by dissolution in lipid membrane regions. Formation of colloidal bilirubin is possible (B25). Aging of the initial, supersaturated (B25) bilirubinate solution is expected to depend (B26) on the procedure of initial solubilization, the time elapsed between lowering the alkaline... 

Some microorganisms produce compounds that can become incorporated into lipid membranes and will facilitate the transmembrane transport of ions, notably K+. These natural products are antibacterial, killing bacteria by lethally altering the transmembrane ion flux. Such antibacterial molecules are called ionophores, or ion carriers, in contrast to other antibacterials, such as polyene antibiotics, which simply produce leakage through the cell membrane. 

Independent of the assumptions A to C the cation selectivity of the membranes in the equilibrium domain is therefore controlled by the ratio of the complex formation constants (6) and should therefore be identical for different types of neutral carrier membranes.18 Figure 2 indicates that there is indeed a close parallelism between the selectivities of solvent polymeric membranes (SPM) and bilayer lipid membranes (BLM) modified with valinomycin 1, nonactin 2, trinactin 5, and tetranac-tin 6 (see also Ref. 18). This is in good agreement with findings from Eisenman s45 and Lev s15 research groups. 

The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars 1 = fosfomycin, 2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = 3-lactam antibiotics). Bactoprenol (BP) is the lipid membrane carrier that transports building blocks across the cytoplasmic membrane M, N-acetylmuramic acid Glc, glucose NAcGIc or G, /V-acetylglucosamine. 

Selectivity sequences in solvents such as water, methanol and ethanol do not guarantee a similar behaviour in the lipid membrane. Experiments have been carried out in attempts to investigate the selective transfer of cations across model membranes, and these are exemplified here by reference to an investigation concerning the cryptands [2.2.2], [3.2.2], [3.3.3] and [2.2.C8]. Two aqueous phases (IN and OUT) were bridged by a chloroform layer into which the carrier can be dissolved. Alkali metal picrate was dissolved in two aqueous layers such that the IN layer was 1000 times more concentrated than the OUT layer. All layers were stirred and the transport monitored via increase in picrate in the OUT layer (UV) and increase in potassium in the OUT layer (atomic absorption). The membrane phase was also analyzed at the end of the experiment.497... 

The above results indicate that in order to maintain the high rate of transmembrane electron transfer, it is necessary to provide efficient neutralization of the arising polarization. For this purpose lipophilic ions and proton carriers were successfully used (see Table 1). These compounds are known to act as the uncouplers of the mitochondrial oxidative phosphorylation and are able to remove the gradients of electric fields across lipid membranes. 

Figure 4. Scheme for proton transfer by plastoquinone as a mobile carrier in membrane lipid. Electrons are transferred one by one to a bound plastoquinone A (PQA) which in turn reduces external plastoquinone. When reduced, the anionic plastoquinone takes up protons to become a hydroquinone which is oxidized by the cytochrome bb f complex on the inside of the membrane to release protons. A second quinone, vitamin K, (KQ) is also involved in chloroplast electron transport, but its role in proton movement is not known. 

Recently, for the transdermal delivery of drugs using carrier systems, attention has been focused on the development of transformable [284,285] or elastic vesicles [12], These vesicles are liposomes that contain surfactants or in general edge activators in addition to phospholipids in their lipid membranes (Figure 10), a fact that... 

Figure 8.29. Ion transport mechanisms through lipid membranes in living cells. There are principally two kinds of transport protein (a) channel proteins, that is, a channelforming ionophore, and (b) carrier proteins, that is, a mobile ion carrier ionophore. The phenomena observed in living cells have much in common with those in artificial polymer membrane ion-selective electrodes. (From Widmer, 1993.)...

Peptidoglycan monomers are assembled on a carrier lipid anchored in the cytoplasmic membrane, and then flipped across the membrane for incorporation into peptidoglycan. The intracellular synthesis of the peptidoglycan momomers is well understood (O Fig. 3) [37]. The peptidoglycan monomers are made from the common cellular building block UDP-GlcNAc... 

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