Carrier transport model

By structural complementarity, dicationic l,4-diazabicyclo[2.2.2]octane (VII) provides an appropriate recognition site for phosphate ions and two stearyl side chains attached to the amines add lipophilic properties 59,60). Such a carrier model can selectively extract nucleotides from aqueous solution to chloroform solution via lipophilic salt formation. The order of nucleotide affinity is ATP > ADP > AMP. The selectivity ratios were 45 for ADP/AMP and 7500 for ATP/AMP at pH 3. The relative transport rate was ATP > ADP > AMP. The ratios were 60 for ATP/AMP and 51 for ADP/AMP. The modes of interaction of ADP and ATP are proposed to be as shown in Fig. 6. 

Fig. 2. The simple asymmetric carrier model for glucose transport. C denotes a sugar-binding site, which can exist in an outward-facing (Co) or an inward-facing (Ci) conformation. Dissociation constants for sugar binding are bja and ejf. Rate constants for carrier re-orientation are c, d, g, and h.

These relationships are identical to Haldane relationships, but unlike the latter, their validity does not derive from a proposed reaction scheme, but merely from the observed hyperbolic dependence of transport rates upon substrate concentration. Krupka showed that these relationships were not obeyed by the set of data previously used by Lieb [64] to reject the simple asymmetric carrier model for glucose transport. Such data therefore cannot be used either to confirm or refute the model. 

Assuming that the simple, four-state asymmetric carrier model does accurately describe the transport process, Lowe and Walmsley [48] have exploited the tempera-... 

Because the rates of sugar binding to and dissociation from the transporter are very rapid compared to the rates of transporter re-orientation, the Michaelis constants for transport by the simple asymmetric carrier model are given by the following equations,... 

According to Gasteiger et al. [59], the correlation coefficient r between bioavailability and HIA is 0.498 for 161 compounds. This conclusion inspires us to propose the use of aqueous solubility, descriptors of HIA models, and some rule-based descriptors to predict first-pass metabolism, to model bioavailability. Another research direction for the prediction of oral bioavailability is to develop separate prediction models for different components involved in oral bioavailability, including passive transcellular transport, paracellular transport, carrier-mediated transport, and first-pass metabolism, and then integrate them together. At present, the development of an integrated model is really difficult or even impossible because the predictions for some mechanisms involved in oral bioavailability are really unreliable. 

Figure 1. A theoretical model for Na+-coupled solute transport. The model assumes a reversible system where only two forms of the carrier are mobile, the empty carrier, C, and the ternary complex, CSNa+. Neither CS nor CNa+ is mobile in either direction so that in absence of Na+ there is no translocation of S. In this model there is random binding of Na+ and S. The net direction of movement will be dictated by the direction of the driving forces. The external and internal milieux are represented by the symbols o and i, respectively.

Following the pioneering work of the Dundee group (LeComber and Spear, 1970 LeComber et ai, 1977 Jones et ai, 1977 Allan et ai, 1977) several researchers (Jan et ai, 1979, 1980 Anderson and Paul, 1982) have interpreted their transport data in terms of a two-carrier model At higher temperatures, transport is by extended states, whereas at lower temperatures NNH in tail states or donor states is pedominant. The transport formulas... 

The simple carrier of Fig. 6 is the simplest model which can account for the range of experimental data commonly found for transport systems. Yet surprisingly, it is not the model that is conventionally used in transport studies. The most commonly used model is some or other form of Fig. 7. In contrast to the simple carrier, the model of Fig. 7, the conventional carrier, assumes that there exist two forms of the carrier-substrate complex, ES, and ES2, and that these can interconvert by the transitions with rate constants g, and g2- Now, our experience with the simple- and complex-pore models should lead to an awareness of the problems in making such an assumption. The transition between ES, and ES2 is precisely such a transition as cannot be identified by steady-state experiments, if the carrier can complex with only one species of transportable substrate. Lieb and Stein [2] have worked out the full kinetic analysis of the conventional carrier model. The derived unidirectional flux equation is exactly equivalent to that derived for the simple carrier Eqn. 30, although the experimentally determinable parameters involving K and R terms have different meanings in terms of the rate constants (the b, /, g and k terms). The appropriate values for the K and R terms in terms of the rate constants are listed in column 3 of Table 3. Thus the simple carrier and the conventional carrier behave identically in... 

People who have worked many years in the transport field have strong intuitive feelings for the correctness of the conventional carrier model. It seems perfectly natural to assume that the substrate-carrier complex formed at one face of the membrane does undergo a transition to a complex which breaks down at the opposite face. Nevertheless, steady-state kinetic experiments cannot justify this assumption and the simpler model yields decidedly simpler kinetic expressions and to a heightened awareness as to the molecular interpretation of the measurable kinetic parameters, as we proceed to discuss. 

Depending on the values of the resistance terms / , one may get very different values for the measured half-saturation concentrations for the various transport procedures. Nevertheless, all these are derivable (if the carrier model holds) from the intrinsic dissociation constant K and the appropriate pair of resistance terms. 

The stoichiometric coupling between the transport of an organic substrate (A) and a cation can be fairly easily represented by the carrier model of cotransport (Fig. 3). It is assumed that the transport is mediated by a membrane component (X) which can alternate between two states X and X", respectively. X is assumed to communicate with the -phase (e.g. extracellular phase) from which it can bind both ligands (A) and (B) to form the two binary complexes AX and BX and also a ternary complex ABX. On the other hand, the state X" communicates with the -phase (e.g. intracellular phase) from which it may bind A and/or B to form the complexes AX, BX" and ABX". The translocation of A and B between the two phases, and ", is assumed to be effected by the interconversion between the two states of each species of X, as has been described in more detail elsewhere (6,10,25,46,47). The transfer of energy between the transfers of A and B via cotransport requires that they move predominantly by ternary complex (ABX), and this implies either that the two binary complexes AX and BX are less ready to interconvert between the -state and "-state, respectively, than is the ternary complex, or that the two binary... 

In addition, the ratio between substrate flux and inhibitor binding is related to the electrical potential in a simple manner which is characteristic for each of the three above-mentioned models for instance, hyperpolarization of the membrane potential should not change this ratio with the gate type model nor with the carrier model 2 (z = — 1) whereas under the same conditions that ratio should increase in carrier model 1 (z = 0). As this relationship does not depend on the composition of the two adjacent fluid phases it should be suitable for further testing the model underlying a given transport mechanism. 

FIG. 11. Diagram of two carrier models, (a) Two-site carrier model. The carrier (T) has two active sites that bind the same substrate (C). Only the uncomplexed and doubly complexed forms of the carrier can move across the membrane, (b) Cotransporter. Similar to (a) but the one active site of the transporter binds the first substrate (C) but the second site binds a second substrate (5). 

The main differences between mobile and fixed types of carriers (see refs. 33, 37, 53, 60-63) have been well summarised in the context of electron and hydrogen transport through the respiratory chain by Chance et They compared the current flow and fluid flow models of Holton and Lunde-gardh with the normal kinetic oxido-reduction model, and pointed out that the latter consists of a series of bimolecular reactions, while the former is equivalent to a unimolecular process. Hence, in the fixed carrier model there is effectively a single chemical channel, whereas in the bimolecular or circulating mobile carrier model there are two chemical channels. 

Membrane-soluble carrier molecules can bind an ion from aqueous solution to create a charged ion/carrier complex within the membrane. This soluble ion then moves down a concentration or electrical gradient to the opposite interface where the ion is released to that solution. Carrier transport is modeled in four kinetic steps (1) the carrier absorbs an ion from solution 1 (2) the ion/carrier complex moves down its gradient to the opposite interface ... 

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