Transport mechanisms structural biology

With the adequacy of lipid bilayer membranes as models for the basic structural motif and hence for the ion transport barrier of biological membranes, studies of channel and carrier ion transport mechanisms across such membranes become of central relevance to transport across cell membranes. The fundamental principles derived from these studies, however, have generality beyond the specific model systems. As noted above and as will be treated below, it is found that selective transport... 

Here, the structure and function of hemopexin, the mechanisms of hemopexin-mediated heme transport, and the biological consequences of this specific transport system are reviewed and questions for future research proposed. This is an opportune time for review since recent advances not only provide new viewpoints and directions but also enable new insights to be derived from earlier work. 

Emphasis is placed here on features of the biological membranes which are implicated in substrate transport. The lipid bilayer in the "gel" state, in the absence of additives, forms an effective barrier against polar ions and water soluble substrates. Changing the fluidity, by phase transition (induced by temperature changes and/or by the addition of foreign ions or molecules) or by the incorporation of additives (cholesterol, for example), profoundly influences the structure and, hence, the transport properties of membranes. This, and the presence of channel or pore forming peptides or proteins, opens the door to a number of transport mechanisms which will be summarized in the following section. 

Apart from these basic rules of thumb, the ability to predict the relationship between molecular structure and transport across biological membranes is limited beyond narrow ranges of known compounds. Confounding factors include inaccurate, incomplete, and/or noncomparable data, and the potential existence of multiple drug transport mechanisms in real biological membranes. In particular, limited QSAR data are available for the specific drug transporters that are considered in the following sections. 

Surfactant Effects on Microbial Membranes and Proteins. Two major factors in the consideration of surfactant toxicity or inhibition of microbial processes are the disruption of cellular membranes b) interaction with lipid structural components and reaction of the surfactant with the enzymes and other proteins essential to the proper functioning of the bacterial cell (61). The basic structural unit of virtually all biological membranes is the phospholipid bilayer (62, 63). Phospholipids are amphiphilic and resemble the simpler nonbiological molecules of commercially available surfactants (i.e., they contain a strongly hydrophilic head group, whereas two hydrocarbon chains constitute their hydrophobic moieties). Phospholipid molecules form micellar double layers. Biological membranes also contain membrane-associated proteins that may be involved in transport mechanisms across cell membranes. 

Schmitt, L. and Tampe, R. (2002) Structure and mechanism of ABC transporters. Current Opinion in Structural Biology, 12 (6), 754-760. 

Several factors may be named as of special importance (1) the amount and composition of organic matter transformed from land surface or biosynthesized in surface waters (2) the transport mechanism involved (3) the biological community structure mediating the transformation mechanisms and (4) physical characteristics of water, such as the water column depth, redox state, temperature, etc. 

The example of this study on a functional membrane system shows the present possibilities in this field. To those used to viewing biological systems at atomic resolution this may seem a rather modest progress, but this would be neglecting the inherent problems posed by the complex nature of membrane structure. In view of the numerous and largely hypothetical proposals for transport mechanisms from other physico-chemical and biochemical sources, however, results like those obtained on the Ca -ATPase system gain strong importance. 

Most biological systems are predominantly water, with other components conferring important structural and mechanical properties. The complexity of the fluid can have a substantial impact on rates of diffusional transport. For example. Chapter 5 discusses the consequences of having self-organized phospholipid phases (i.e., membrane bilayers) in systems that are primarily composed of water. Membranes separate the medium into smaller aqueous compartments, which remain distinct because the membrane permits the diffusion of only certain types of molecules between the compartments. Complex fluid phases have diverse roles in biological systems hyaluronic acid forms a viscoelastic gel within the eye (vitreous humor) that provides both mechanical structure and transparency actin monomers and polymers within the cytoplasm control cell shape and internal architecture. Drug molecules often must diffuse through these complex fluids in order to reach their site of action. 

The biosynthesis of a variety of biologically active peptides proceeds nucleic acid-free on protein templates (IK Peptide synthetases generally activate an acceptor amino acid by formation of amino-acyl adenylates or phosphates, which will be stabilized in an enzyne-aminoacylation step, similar as in tRNA-aminoacylation. Reaction with a donor peptide, which may be covalently bound, leads to a specific chain elongation. While small peptides like glutathione are formed by "one-step"-synthetases, more complex structures like gramicidin S are produced by multienzvme systems, which may contain multifunctional polypeptides. Characteristic features of such systems are 1.)activation as aminoacyl adenylates, 2.) aminoacylation of enzyme thiol-groups, 3.) covalently bound peptide intermediates and 4.) a specific intrinsic transport mechanism similar to the biosynthesis of fatty acids. 

Whatever the transport mechanism is, it should be realized that biological membranes are dynamic structures that respond to ambient changes. Thus, a membrane often responds to solute-manbrane interactions through a feedback mechanism. 

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