The molecular mechanism of transport

This work was supported by United States Public Health Service National Institutes of Health Grant GM24784. 

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Bayliss, R., Corbett, A.El. and Stewart, M. (2000) The molecular mechanism of transport of macromolecules through nuclear pore complexes. Traffic, 1, 448 156. 

Binding of hydrophobic molecules by specific protein carriers appears to be a very efficient mechanism to increase both solubility and transport of these molecular messengers in a hydrophilic medium. OBPs and CSPs may represent a successful application of this principle. In particular, the molecular mechanisms of transport of hydrophobic molecules may be more ancient than that most ancient of senses, olfaction. The olfactory system may have developed to extract the hydrophobic odorants from the air environment and optimize their transport and delivery to sensory cells. 

As mentioned earlier, the underlying mechanisms for many of the transporter-mediated interactions are not fully understood and remain elusive at the present time. With the limited knowledge on the molecular mechanisms of transporter-mediated interaction and the fact that many inhibitors and inducers can simultaneously affect both drug transporters and CYP enzymes, it is difficult to quantitatively differentiate transporter-mediated interactions from CYP-mediated interactions. From the literature, it becomes clear that evidence of transporter-mediated dmg interactions, with few exceptions, is often indirectly derived from in vitro transport studies with cellular culture models and heterologous expression systems. 

This, however, introduces a number of complications, and for information on the molecular mechanics of transport it would be desirable to work with a simpler system, such as membrane vesicles, and such experiments are in progress (84). Many unresolved questions in siderophore transport await resolution. 

Studies of the molecular mechanism of transport of the carriers of the mitochondrial membrane can be divided into two categories. One includes kinetic studies and the other includes structural studies, which rely either on the availability of pure isolated carrier protein or involve careful and detailed studies of substrate specificity and the effects of minor modifications of substrate structure in an attempt to specify the structural requirements of the catalytic site. 

However, since the proportion of most metabohtes present as free acid at pH 7 is low, it is likely that the carriers have separate binding sites for protons and anions. The relationships between proton concentrations, substrate concentrations and rates of transport have been examined in order to gain insight into the molecular mechanisms of transport for the glutamate, pyruvate and phosphate carriers. 

Although the author of this review is far from being an expert in the field of biomembrane research, some literature studied so far seems to indicate that the molecular mechanisms of the active ion transport are still not known 107). 

The above statements are valid for monomolecular layers only. In the case of polymer films with layer thickness into the p-range, as are usually produced by electropolymerization, account must also be taken of the fact that the charge transport is dependent on both the electron exchange reactions between neighbouring oxidized and reduced sites and the flux of counterions in keeping with the principle of electroneutrality Although the molecular mechanisms of these processes... 

Animals cannot synthesize carotenoids de novo. To deposit carotenoids in the proper tissues in the proper amounts, they must acquire carotenoids from dietary sources and transport them to target sites. Knowledge of the molecular mechanisms of carotenoid transport, however, is still... 

Rudnick, G. and Wall, S.C., The molecular mechanism of ecstasy [3,4-methylenedioxy-metham-phetamine (MDMA)] serotonin transporters are targets for MDMA-induced serotonin release, Proc. Natl. Acad. Sci. U.S.A. 89(5), 1817-1821, 1992. 

In passing, it is good to emphasise that the above analysis illustrates the limitations of the widely used Nernst diffusion layer concept. This concept assumes that there is a certain thin layer of static liquid adjacent to the solid plane under consideration at x = 0. Inside this layer, diffusion is supposed to be the sole mechanism of transport, and, outside the layer, the concentration of the diffusing component is constant, as a result of the convection in the liquid. We have seen that, in contradiction with this oversimplified picture, molecular diffusion and liquid motion are not spatially separated, and that the thickness... 

Proton conductivities of 0.1 S cm at high excess water contents in current PEMs stem from the concerted effect of a high concentration of free protons, high liquid-like proton mobility, and a well-connected cluster network of hydrated pathways. i i i i Correspondingly, the detrimental effects of membrane dehydration are multifold. It triggers morphological transitions that have been studied recently in experiment and theory.2 .i29.i ,i62 water contents below the percolation threshold, the well-hydrated pathways cease to span the complete sample, and poorly hydrated channels control the overall transports ll Moreover, the structure of water and the molecular mechanisms of proton transport change at low water contents. 

Stephen J. Paddison received a B.Sc.(Hon.) in Chemical Physics and a Ph.D. (1996) in Physical/Theoretical Chemistry from the University of Calgary, Canada. He was, subsequently, a postdoctoral fellow and staff member in the Materials Science Division at Los Alamos National Laboratory, where he conducted both experimental and theoretical investigations of sulfonic acid polymer electrolyte membranes. This work was continued while he was part of Motorola s Computational Materials Group in Los Alamos. He is currently an Assistant Professor in the Chemistry and Materials Science Departments at the University of Alabama in Huntsville, AL. Research interests continue to be in the development and application of first-principles and statistical mechanical methods in understanding the molecular mechanisms of proton transport in fuel-cell materials. 

Although less frequently compared with the reported cases of cytochrome P450 (CYP)-mediated dmg interactions, transporter-mediated dmg interactions have been reported in animals and humans. Unlike the CYP-mediated dmg interactions, which can be readily defined by inhibition or induction of CYP enzymes, the examples of transporter-mediated dmg interactions are often less conclusive (5-7). In many cases, transporter-mediated interactions are postulated on the basis of circumstantial evidence. Sometimes they are referred to as transporter-mediated dmg interactions because they cannot be explained by CYP inhibition or induction. Owing to the broad overlap in substrate specificity, many inhibitors and inducers can simultaneously affect both dmg transporters and CYP enzymes. Therefore, care should be exercised when exploring the underlying mechanisms of dmg interactions. The main purpose of this chapter is to explore the molecular mechanisms of dmg interactions involving dmg transporters. While the discussion will be focused predominantly on human data, examples from animal studies will also be used to assist in our understanding of the transporter-mediated dmg interactions. 

Artificial asymmetric membranes composed of outer membranes of various species of Gram-negative bacteria and an inner leaflet of various phospholipids have been prepared using the Montal-Mueller technique [65]. Such planar bilayers have been used, for example, to study the molecular mechanism of polymyxin B-mem-brane interactions. A direct correlation between surface charge density and self-promoted transport has been found [66]. 

H. Harder, then in our laboratory but now at George Washington University, was responsible for these studies. He also checked that the synthesis of precursor molecules for DNA, and the transport of these across membranes was not responsible for the inhibition. He has more recently shown that the ability of the DNA to act as a template for new synthesis is strongly inhibited by the platinum drug. These results can be most reasonably explained by the hypothesis that the anticancer activity of the platinum drugs arises from a primary attack on DNA. The battle to discover the molecular mechanism of action was, therefore, joined on the field of metal complex interactions with DNA, and numerous other laboratories entered the fray. The booty has been rich, embarrasingly so. 

Fig. 7 Possible model for the molecular mechanism of multidrug transporters. MDR1-P-glycoprotein (substrates are recognized in, or near to the membrane lipid phase). Abbreviations hD hydrophobic drugs, PL Phospholipids. (Reproduced from [4])...

However, changes in the potential energy of intermolecular interactions are not uniquely separable. There is an ambiguity in defining the heat flow for open systems. We may split u into a diffusive part and a conductive part in several ways and define various numbers of heat flows. In the molecular mechanism of energy transport, the energy... 

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