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Biological membranes are effective barriers protecting the cytoplasm of a cell and all its functional components from the surrounding medium. Only small uncharged molecules such as water or urea, or larger hydrophobic compounds such as benzene can diffuse freely through the nonpolar double-layer of a membrane. Passage of larger polar molecules, to provide the cell with nutrients, for example carbohydrates or amino acids, or of ions, to maintain the membrane potential, is impossible without special transport mechanisms. The different types of transport mechanism found in biological systems can be divided into passive transport that follows the electrochemical gradient across the membrane, and active transport that proceeds in the opposite direction. The latter requires energy often supplied by hydrolysis of ATP.

An effective means by which ions can passively penetrate a biological membrane is passage through a pore created by a transmembrane protein, an example of which is gramicidin A. This linear helical peptide is composed of 15 alternating l- and D-amino acids. Self-assembly of two gramicidin A molecules in the interior of a cell membrane results in formation of a channel through which up to 107 monocations can pass in per second (Figure B.6.1). Another class of transmembrane protein, termed porines, form ion channels consisting of 16 or 18 cyclically arranged ¿S-sheets, the so-called ^-barrels. An interesting property of porines is that ion transport depends on the membrane potential - above or below a certain potential the porine channels close. The opening or closing of an ion channel can be triggered by the binding of a suitable substrate to the extracellular part of the transmembrane protein. A typical example is the nicotinic acetylcho-line receptor responsible for transfer of nerve pulses across synapses. This transfer starts with release of acetylcholine from the pre-synaptic membrane into the synaptic gap. Binding of the neurotransmitter to the acetyl-choline receptor located in the post-synaptic membrane causes the opening of an ion channel and, because Na+ ions now permeate the membrane, a change in membrane potential.

Ionophores such as valinomycin also transport charged substrates across membranes. These often cyclic, low-molecular weight compounds do not

Fig. B.6.1. Schematic representation of the action of gramicidin A (a), an ionophore (b), and a ligand-controlled ion channel (c) in the transport of ions across a biological membrane.

form ion channels, however, but use a carrier mechanism for ion transport. As a consequence, the transport rate is much slower than a flow of ions through a channel. Transport selectivity is achieved as a result of the different affinities of the ionophores for different ions.

The action of transmembrane proteins capable of an active ion transport is more complex. The Na+/K+-ATP-ase, for example, the enzyme responsible for maintaining the high K+ concentration inside cells, and the high Na+ concentration outside, is made up of two pairs of large (a) and small (b) proteins. The a-proteins span the membrane and occur in different conformations in the presence of Na+ or K+. Phosphorylation of the Na+/ enzyme complex by ATP leads to conformational reorganization of the protein, whereupon sodium ions are transported to the extracellular side of the membrane where they are released. Subsequently, binding of K+ in conjunction with dephosphorylation of the enzyme triggers a reversal of the conformational change and a transport of potassium into the cell interior. The overall process has a turnover of ca 150 and consists of a transport of three Na+ ions out of the cell and two K+ ions into the cell with simultaneous consumption of one molecule of ATP. Light is another energy source used for active membrane transport of ions by, for example, bacter-iorhodopsin in halobacteria.

Model systems have been developed for many of these ion-transport mechanisms in the context of bioorganic chemistry. Examples are the cyclic peptides, described by M. R. Ghadiri et al., that have antibiotic activity similar to that of ionophores, a property that is most probably caused by the ability of these peptides to self-assemble inside biological membranes into channels [1]. Other compounds able to induce the formation of membrane pores are the bouquet-molecules introduced by J.-M. Lehn [2]. Artificial b-barrels have been developed by S. Matile's group [3]. Many host molecules used in bioorganic chemistry can serve as carriers for ions across membranes and have even made possible the development of systems with which active ion transport can be achieved [4].

References

1 S. Fernandez-Lopez, H.-S. Kim, E. C. Choi, M. Delgado, J. R. Granja, A. Khasanov, K. Kraehenbuehl, G. Long, D. A. Weinberger, K. M. Wilcoxen, M. R. Ghadiri, Nature 2001, 412, 452-455.

2 M. J. Pregel, L. Jumen, J.-M. Lehn, Angew. Chem. 1992, 104, 1695-1697; Angew. Chem. Int. Ed. Engl. 1992, 31, 1637-1640; J.

Canceill, L. Jullien, L. Lacombe, J.-M. Lehn, Helv. Chim. Acta 1992, 75, 791-812; L. Jullien, T. Lazrak, J. Canceill, L. Lacombe, J.-M. Lehn, J. Chem. Soc., Perkin Trans 2 1993, 1011-1020.

4 M. Okahara, Y. Nakatsuji, Top. Curr. Chem. 1985, 128, 37-59.

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